EP3548062B1 - New compounds as peptidic glp1/glucagon/gip receptor agonists - Google Patents
New compounds as peptidic glp1/glucagon/gip receptor agonists Download PDFInfo
- Publication number
- EP3548062B1 EP3548062B1 EP17821489.6A EP17821489A EP3548062B1 EP 3548062 B1 EP3548062 B1 EP 3548062B1 EP 17821489 A EP17821489 A EP 17821489A EP 3548062 B1 EP3548062 B1 EP 3548062B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- ethoxy
- carboxy
- seq
- compound
- amino acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 title claims description 131
- 102000051325 Glucagon Human genes 0.000 title claims description 48
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 title claims description 48
- 229960004666 glucagon Drugs 0.000 title claims description 48
- 108060003199 Glucagon Proteins 0.000 title claims description 41
- 239000000018 receptor agonist Substances 0.000 title description 8
- 229940044601 receptor agonist Drugs 0.000 title description 8
- 101100337060 Caenorhabditis elegans glp-1 gene Proteins 0.000 title 1
- -1 pentadecanyl Chemical group 0.000 claims description 103
- 238000000034 method Methods 0.000 claims description 65
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 64
- 239000008103 glucose Substances 0.000 claims description 64
- 230000000694 effects Effects 0.000 claims description 49
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 claims description 44
- 150000003839 salts Chemical class 0.000 claims description 38
- 206010012601 diabetes mellitus Diseases 0.000 claims description 37
- 125000000539 amino acid group Chemical group 0.000 claims description 31
- 239000012453 solvate Substances 0.000 claims description 31
- 208000008589 Obesity Diseases 0.000 claims description 29
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 claims description 28
- 102100039994 Gastric inhibitory polypeptide Human genes 0.000 claims description 28
- 235000020824 obesity Nutrition 0.000 claims description 27
- 108010036598 gastric inhibitory polypeptide receptor Proteins 0.000 claims description 25
- 108010063919 Glucagon Receptors Proteins 0.000 claims description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 22
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 21
- 102100040890 Glucagon receptor Human genes 0.000 claims description 19
- 230000015572 biosynthetic process Effects 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 claims description 13
- 102100032882 Glucagon-like peptide 1 receptor Human genes 0.000 claims description 13
- 239000013543 active substance Substances 0.000 claims description 13
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 claims description 12
- 239000004480 active ingredient Substances 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 7
- 201000009104 prediabetes syndrome Diseases 0.000 claims description 7
- 206010020772 Hypertension Diseases 0.000 claims description 6
- 201000001421 hyperglycemia Diseases 0.000 claims description 6
- 206010022489 Insulin Resistance Diseases 0.000 claims description 5
- 206010018429 Glucose tolerance impaired Diseases 0.000 claims description 4
- 208000006011 Stroke Diseases 0.000 claims description 4
- 230000003834 intracellular effect Effects 0.000 claims description 4
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 3
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 3
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 3
- 208000029078 coronary artery disease Diseases 0.000 claims description 3
- 108010063245 glucagon-like peptide 1 (7-36)amide Proteins 0.000 claims description 3
- 208000001280 Prediabetic State Diseases 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 208000030613 peripheral artery disease Diseases 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 136
- 108090000765 processed proteins & peptides Proteins 0.000 description 92
- 239000003981 vehicle Substances 0.000 description 84
- 241000699670 Mus sp. Species 0.000 description 76
- 210000004369 blood Anatomy 0.000 description 67
- 239000008280 blood Substances 0.000 description 67
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 63
- JUFFVKRROAPVBI-PVOYSMBESA-N chembl1210015 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)N[C@H]1[C@@H]([C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@]3(O[C@@H](C[C@H](O)[C@H](O)CO)[C@H](NC(C)=O)[C@@H](O)C3)C(O)=O)O2)O)[C@@H](CO)O1)NC(C)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 JUFFVKRROAPVBI-PVOYSMBESA-N 0.000 description 55
- 239000011347 resin Substances 0.000 description 55
- 229920005989 resin Polymers 0.000 description 55
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 52
- 108010011459 Exenatide Proteins 0.000 description 51
- 239000012071 phase Substances 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 47
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 46
- 229960001519 exenatide Drugs 0.000 description 46
- 238000011282 treatment Methods 0.000 description 45
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 44
- 102100040918 Pro-glucagon Human genes 0.000 description 42
- 229940024606 amino acid Drugs 0.000 description 41
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 39
- 241001465754 Metazoa Species 0.000 description 39
- 235000001014 amino acid Nutrition 0.000 description 38
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 32
- 238000002296 dynamic light scattering Methods 0.000 description 27
- 150000001413 amino acids Chemical class 0.000 description 26
- 239000000243 solution Substances 0.000 description 26
- 102000004196 processed proteins & peptides Human genes 0.000 description 25
- 238000010162 Tukey test Methods 0.000 description 24
- 238000001543 one-way ANOVA Methods 0.000 description 24
- 239000000203 mixture Substances 0.000 description 23
- 102000005962 receptors Human genes 0.000 description 23
- 108020003175 receptors Proteins 0.000 description 23
- 102000004877 Insulin Human genes 0.000 description 22
- 108090001061 Insulin Proteins 0.000 description 22
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 22
- 238000012360 testing method Methods 0.000 description 22
- 238000005259 measurement Methods 0.000 description 21
- 230000009435 amidation Effects 0.000 description 20
- 238000007112 amidation reaction Methods 0.000 description 20
- 229940125396 insulin Drugs 0.000 description 20
- 239000002245 particle Substances 0.000 description 20
- 230000001684 chronic effect Effects 0.000 description 19
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 18
- 239000002953 phosphate buffered saline Substances 0.000 description 17
- 230000009467 reduction Effects 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 17
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- 210000000577 adipose tissue Anatomy 0.000 description 16
- 239000000556 agonist Substances 0.000 description 16
- 125000003275 alpha amino acid group Chemical group 0.000 description 16
- 239000007853 buffer solution Substances 0.000 description 16
- 238000009826 distribution Methods 0.000 description 16
- 210000004185 liver Anatomy 0.000 description 16
- 238000010254 subcutaneous injection Methods 0.000 description 16
- 239000003112 inhibitor Substances 0.000 description 15
- 238000007920 subcutaneous administration Methods 0.000 description 15
- 230000037396 body weight Effects 0.000 description 14
- 125000005647 linker group Chemical group 0.000 description 14
- 239000000126 substance Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 230000003993 interaction Effects 0.000 description 12
- 235000020925 non fasting Nutrition 0.000 description 12
- 238000007619 statistical method Methods 0.000 description 12
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 11
- 125000003277 amino group Chemical group 0.000 description 11
- 238000003556 assay Methods 0.000 description 11
- 235000018102 proteins Nutrition 0.000 description 11
- 102000004169 proteins and genes Human genes 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- JADVWWSKYZXRGX-UHFFFAOYSA-M thioflavine T Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C1=[N+](C)C2=CC=C(C)C=C2S1 JADVWWSKYZXRGX-UHFFFAOYSA-M 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 10
- 108010082126 Alanine transaminase Proteins 0.000 description 10
- 208000001145 Metabolic Syndrome Diseases 0.000 description 10
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 10
- 230000001154 acute effect Effects 0.000 description 10
- 239000000872 buffer Substances 0.000 description 10
- 235000005911 diet Nutrition 0.000 description 10
- 230000037213 diet Effects 0.000 description 10
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 10
- 230000037406 food intake Effects 0.000 description 10
- 235000012631 food intake Nutrition 0.000 description 10
- 229960004452 methionine Drugs 0.000 description 10
- 239000000523 sample Substances 0.000 description 10
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 9
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 9
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
- 239000003755 preservative agent Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 8
- 239000004472 Lysine Substances 0.000 description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- 230000004913 activation Effects 0.000 description 8
- 230000008859 change Effects 0.000 description 8
- 235000012000 cholesterol Nutrition 0.000 description 8
- 230000008878 coupling Effects 0.000 description 8
- 238000010168 coupling process Methods 0.000 description 8
- 238000005859 coupling reaction Methods 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 238000011068 loading method Methods 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 238000010532 solid phase synthesis reaction Methods 0.000 description 8
- 239000003643 water by type Substances 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- 230000009471 action Effects 0.000 description 7
- 230000000740 bleeding effect Effects 0.000 description 7
- 238000003776 cleavage reaction Methods 0.000 description 7
- 239000003937 drug carrier Substances 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 239000004220 glutamic acid Substances 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 7
- 238000010647 peptide synthesis reaction Methods 0.000 description 7
- 230000002265 prevention Effects 0.000 description 7
- 230000007017 scission Effects 0.000 description 7
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 description 6
- 101001015516 Homo sapiens Glucagon-like peptide 1 receptor Proteins 0.000 description 6
- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 description 6
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 102000003729 Neprilysin Human genes 0.000 description 6
- 108090000028 Neprilysin Proteins 0.000 description 6
- 230000000845 anti-microbial effect Effects 0.000 description 6
- 230000009286 beneficial effect Effects 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 230000006872 improvement Effects 0.000 description 6
- 238000001802 infusion Methods 0.000 description 6
- 230000001404 mediated effect Effects 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 229930182817 methionine Natural products 0.000 description 6
- 230000036515 potency Effects 0.000 description 6
- 238000011421 subcutaneous treatment Methods 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 5
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 5
- 241000282414 Homo sapiens Species 0.000 description 5
- 108010019598 Liraglutide Proteins 0.000 description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- 230000003178 anti-diabetic effect Effects 0.000 description 5
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 5
- 210000004899 c-terminal region Anatomy 0.000 description 5
- 231100000762 chronic effect Toxicity 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000009792 diffusion process Methods 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 239000005022 packaging material Substances 0.000 description 5
- 239000004033 plastic Substances 0.000 description 5
- 229920003023 plastic Polymers 0.000 description 5
- 238000002953 preparative HPLC Methods 0.000 description 5
- 230000002335 preservative effect Effects 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 230000028327 secretion Effects 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 5
- ZBONYRRPQHNTOJ-LCALOIESSA-N (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-6-[[(4S)-4-[[(4S)-4-(hexadecanoylamino)-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoyl]amino]-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoyl]amino]hexanoic acid Chemical compound C(C)(C)(C)OC([C@H](CCC(=O)NCCCC[C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C=2C=CC=CC1=2)NC(CC[C@@H](C(=O)OC(C)(C)C)NC(CCCCCCCCCCCCCCC)=O)=O)=O ZBONYRRPQHNTOJ-LCALOIESSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- AIRYAONNMGRCGJ-FHFVDXKLSA-N CC[C@H](C)[C@H](NC(=O)CN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H]1CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc3c[nH]cn3)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc3ccccc3)C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](Cc3c[nH]cn3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc3ccc(O)cc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC2=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N2CCC[C@H]2C(=O)N[C@@H]([C@@H](C)O)C(O)=O)NC1=O)[C@@H](C)O)[C@@H](C)CC Chemical compound CC[C@H](C)[C@H](NC(=O)CN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H]1CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc3c[nH]cn3)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc3ccccc3)C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](Cc3c[nH]cn3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc3ccc(O)cc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC2=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N2CCC[C@H]2C(=O)N[C@@H]([C@@H](C)O)C(O)=O)NC1=O)[C@@H](C)O)[C@@H](C)CC AIRYAONNMGRCGJ-FHFVDXKLSA-N 0.000 description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical class NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 4
- 101001040075 Homo sapiens Glucagon receptor Proteins 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- 108010057186 Insulin Glargine Proteins 0.000 description 4
- COCFEDIXXNGUNL-RFKWWTKHSA-N Insulin glargine Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(=O)NCC(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 COCFEDIXXNGUNL-RFKWWTKHSA-N 0.000 description 4
- FFEARJCKVFRZRR-UHFFFAOYSA-N L-Methionine Natural products CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 description 4
- 229930195722 L-methionine Natural products 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 102400000319 Oxyntomodulin Human genes 0.000 description 4
- 101800001388 Oxyntomodulin Proteins 0.000 description 4
- 239000004793 Polystyrene Substances 0.000 description 4
- 230000001270 agonistic effect Effects 0.000 description 4
- 239000004599 antimicrobial Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 4
- 229940088597 hormone Drugs 0.000 description 4
- 239000005556 hormone Substances 0.000 description 4
- 230000001976 improved effect Effects 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 230000000968 intestinal effect Effects 0.000 description 4
- 210000004153 islets of langerhan Anatomy 0.000 description 4
- 229960002701 liraglutide Drugs 0.000 description 4
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- PXZWGQLGAKCNKD-DPNMSELWSA-N molport-023-276-326 Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 PXZWGQLGAKCNKD-DPNMSELWSA-N 0.000 description 4
- 208000015122 neurodegenerative disease Diseases 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 108010029667 pramlintide Proteins 0.000 description 4
- NRKVKVQDUCJPIZ-MKAGXXMWSA-N pramlintide acetate Chemical compound C([C@@H](C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CCCCN)[C@@H](C)O)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NRKVKVQDUCJPIZ-MKAGXXMWSA-N 0.000 description 4
- 238000004007 reversed phase HPLC Methods 0.000 description 4
- 239000007790 solid phase Substances 0.000 description 4
- CTYHQVFFQRDJSN-LHEWISCISA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-6-[[(4-methoxyphenyl)-diphenylmethyl]amino]hexanoic acid Chemical compound C1=CC(OC)=CC=C1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)NCCCC[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 CTYHQVFFQRDJSN-LHEWISCISA-N 0.000 description 3
- OYXZPXVCRAAKCM-SANMLTNESA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(1-tritylimidazol-4-yl)propanoic acid Chemical compound C1=NC(C[C@H](NC(=O)OC(C)(C)C)C(O)=O)=CN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 OYXZPXVCRAAKCM-SANMLTNESA-N 0.000 description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- FZTIWOBQQYPTCJ-UHFFFAOYSA-N 4-[4-(4-carboxyphenyl)phenyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(O)=O)C=C1 FZTIWOBQQYPTCJ-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 201000001320 Atherosclerosis Diseases 0.000 description 3
- 238000011740 C57BL/6 mouse Methods 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- 239000012981 Hank's balanced salt solution Substances 0.000 description 3
- 241000270431 Heloderma suspectum Species 0.000 description 3
- 101000886868 Homo sapiens Gastric inhibitory polypeptide Proteins 0.000 description 3
- 208000013016 Hypoglycemia Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- XVVOERDUTLJJHN-UHFFFAOYSA-N Lixisenatide Chemical compound C=1NC2=CC=CC=C2C=1CC(C(=O)NC(CC(C)C)C(=O)NC(CCCCN)C(=O)NC(CC(N)=O)C(=O)NCC(=O)NCC(=O)N1C(CCC1)C(=O)NC(CO)C(=O)NC(CO)C(=O)NCC(=O)NC(C)C(=O)N1C(CCC1)C(=O)N1C(CCC1)C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)CC)NC(=O)C(NC(=O)C(CC(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)C(NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(CCC(O)=O)NC(=O)C(CCC(O)=O)NC(=O)C(CCSC)NC(=O)C(CCC(N)=O)NC(=O)C(CCCCN)NC(=O)C(CO)NC(=O)C(CC(C)C)NC(=O)C(CC(O)=O)NC(=O)C(CO)NC(=O)C(NC(=O)C(CC=1C=CC=CC=1)NC(=O)C(NC(=O)CNC(=O)C(CCC(O)=O)NC(=O)CNC(=O)C(N)CC=1NC=NC=1)C(C)O)C(C)O)C(C)C)CC1=CC=CC=C1 XVVOERDUTLJJHN-UHFFFAOYSA-N 0.000 description 3
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000008351 acetate buffer Substances 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 239000003472 antidiabetic agent Substances 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 229920001971 elastomer Polymers 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 235000013922 glutamic acid Nutrition 0.000 description 3
- 210000002216 heart Anatomy 0.000 description 3
- 235000009200 high fat diet Nutrition 0.000 description 3
- 230000002218 hypoglycaemic effect Effects 0.000 description 3
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 3
- 239000000859 incretin Substances 0.000 description 3
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 description 3
- 229960002869 insulin glargine Drugs 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 229960001093 lixisenatide Drugs 0.000 description 3
- 108010004367 lixisenatide Proteins 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 210000000496 pancreas Anatomy 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 229920002223 polystyrene Polymers 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002464 receptor antagonist Substances 0.000 description 3
- 229940044551 receptor antagonist Drugs 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- HYTPDMFFHVZBOR-VNXMGFANSA-N (1r,2s,3s,4r,5r)-5-[4-chloro-3-[(4-ethoxy-3-fluorophenyl)methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol Chemical compound C1=C(F)C(OCC)=CC=C1CC1=CC([C@]23O[C@](CO)(CO2)[C@@H](O)[C@H](O)[C@H]3O)=CC=C1Cl HYTPDMFFHVZBOR-VNXMGFANSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- JDDWRLPTKIOUOF-UHFFFAOYSA-N 9h-fluoren-9-ylmethyl n-[[4-[2-[bis(4-methylphenyl)methylamino]-2-oxoethoxy]phenyl]-(2,4-dimethoxyphenyl)methyl]carbamate Chemical compound COC1=CC(OC)=CC=C1C(C=1C=CC(OCC(=O)NC(C=2C=CC(C)=CC=2)C=2C=CC(C)=CC=2)=CC=1)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 JDDWRLPTKIOUOF-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 0 CCCCCCCCCCCCCCCC(N[C@@](CCC(N[C@@](CCC(*)=O)C(O)=O)=O)C(O)=O)=O Chemical compound CCCCCCCCCCCCCCCC(N[C@@](CCC(N[C@@](CCC(*)=O)C(O)=O)=O)C(O)=O)=O 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 229920000089 Cyclic olefin copolymer Polymers 0.000 description 2
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 2
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 description 2
- LCDDAGSJHKEABN-MLGOLLRUSA-N Evogliptin Chemical compound C1CNC(=O)[C@@H](COC(C)(C)C)N1C(=O)C[C@H](N)CC1=CC(F)=C(F)C=C1F LCDDAGSJHKEABN-MLGOLLRUSA-N 0.000 description 2
- BZCALJIHZVNMGJ-HSZRJFAPSA-N Fasiglifam Chemical compound CC1=CC(OCCCS(C)(=O)=O)=CC(C)=C1C1=CC=CC(COC=2C=C3OC[C@@H](CC(O)=O)C3=CC=2)=C1 BZCALJIHZVNMGJ-HSZRJFAPSA-N 0.000 description 2
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 108091016366 Histone-lysine N-methyltransferase EHMT1 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 108010065920 Insulin Lispro Proteins 0.000 description 2
- 108010041872 Islet Amyloid Polypeptide Chemical class 0.000 description 2
- 102000036770 Islet Amyloid Polypeptide Human genes 0.000 description 2
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- 108010092277 Leptin Proteins 0.000 description 2
- 102000016267 Leptin Human genes 0.000 description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 2
- 235000021314 Palmitic acid Nutrition 0.000 description 2
- 101800001672 Peptide YY(3-36) Proteins 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 108010058003 Proglucagon Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- ZXOCGDDVNPDRIW-NHFZGCSJSA-N Tofogliflozin Chemical compound O.C1=CC(CC)=CC=C1CC1=CC=C(CO[C@@]23[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C2=C1 ZXOCGDDVNPDRIW-NHFZGCSJSA-N 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 239000002535 acidifier Substances 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 125000002015 acyclic group Chemical group 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000008484 agonism Effects 0.000 description 2
- DAYKLWSKQJBGCS-NRFANRHFSA-N aleglitazar Chemical compound C1=2C=CSC=2C(C[C@H](OC)C(O)=O)=CC=C1OCCC(=C(O1)C)N=C1C1=CC=CC=C1 DAYKLWSKQJBGCS-NRFANRHFSA-N 0.000 description 2
- 229950010157 aleglitazar Drugs 0.000 description 2
- 230000003113 alkalizing effect Effects 0.000 description 2
- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000003524 antilipemic agent Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 229960001230 asparagine Drugs 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- 125000000613 asparagine group Chemical group N[C@@H](CC(N)=O)C(=O)* 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- 229940090047 auto-injector Drugs 0.000 description 2
- 238000005311 autocorrelation function Methods 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 239000011111 cardboard Substances 0.000 description 2
- 206010061592 cardiac fibrillation Diseases 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000000423 cell based assay Methods 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000007979 citrate buffer Substances 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 208000012696 congenital leptin deficiency Diseases 0.000 description 2
- 239000007819 coupling partner Substances 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 229960003834 dapagliflozin Drugs 0.000 description 2
- 230000006240 deamidation Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 230000006806 disease prevention Effects 0.000 description 2
- 239000002934 diuretic Substances 0.000 description 2
- 229940030606 diuretics Drugs 0.000 description 2
- 210000003890 endocrine cell Anatomy 0.000 description 2
- 229950011259 evogliptin Drugs 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 230000002600 fibrillogenic effect Effects 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 208000020694 gallbladder disease Diseases 0.000 description 2
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 2
- 230000014101 glucose homeostasis Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 208000019622 heart disease Diseases 0.000 description 2
- 102000050325 human granulocyte inhibitory Human genes 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000004026 insulin derivative Substances 0.000 description 2
- 229960002068 insulin lispro Drugs 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229960002725 isoflurane Drugs 0.000 description 2
- 229960000310 isoleucine Drugs 0.000 description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- 229940039781 leptin Drugs 0.000 description 2
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 2
- UGOZVNFCFYTPAZ-IOXYNQHNSA-N levemir Chemical compound CCCCCCCCCCCCCC(=O)NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)CNC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=2N=CNC=2)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=2N=CNC=2)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=2C=CC=CC=2)C(C)C)CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(C)C)CSSC[C@H](NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC2=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H](CSSC1)C(=O)N[C@@H](CC(N)=O)C(O)=O)CC1=CC=C(O)C=C1 UGOZVNFCFYTPAZ-IOXYNQHNSA-N 0.000 description 2
- 229960002397 linagliptin Drugs 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000003908 liver function Effects 0.000 description 2
- 230000033001 locomotion Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 208000001022 morbid obesity Diseases 0.000 description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 230000000324 neuroprotective effect Effects 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- MKMPWKUAHLTIBJ-ISTRZQFTSA-N omarigliptin Chemical compound C1([C@H]2OC[C@@H](C[C@@H]2N)N2CC3=CN(N=C3C2)S(=O)(=O)C)=CC(F)=CC=C1F MKMPWKUAHLTIBJ-ISTRZQFTSA-N 0.000 description 2
- 229940125395 oral insulin Drugs 0.000 description 2
- 239000000123 paper Substances 0.000 description 2
- 238000003921 particle size analysis Methods 0.000 description 2
- 239000000813 peptide hormone Substances 0.000 description 2
- 125000001151 peptidyl group Chemical group 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 239000008024 pharmaceutical diluent Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229960003611 pramlintide Drugs 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000006920 protein precipitation Effects 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 230000036186 satiety Effects 0.000 description 2
- 235000019627 satiety Nutrition 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 108010033693 saxagliptin Proteins 0.000 description 2
- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 description 2
- 201000002859 sleep apnea Diseases 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000012430 stability testing Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 229940099093 symlin Drugs 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 description 2
- 230000002123 temporal effect Effects 0.000 description 2
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 2
- 229940127279 trajenta Drugs 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 0.000 description 2
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 2
- 229960001254 vildagliptin Drugs 0.000 description 2
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- 239000002023 wood Substances 0.000 description 2
- PCOMIRCNMMNOAP-CQSZACIVSA-N (1s)-1-[5-[[3-(2-methylpyridin-3-yl)oxy-5-pyridin-2-ylsulfanylpyridin-2-yl]amino]-1,2,4-thiadiazol-3-yl]ethane-1,2-diol Chemical compound CC1=NC=CC=C1OC1=CC(SC=2N=CC=CC=2)=CN=C1NC1=NC([C@H](O)CO)=NS1 PCOMIRCNMMNOAP-CQSZACIVSA-N 0.000 description 1
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 1
- YEKUUBPJRPXMBM-PTCFZACGSA-N (2S)-5-[[(5S)-5-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-[[2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]acetyl]amino]-3-hydroxybutanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-6-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-carbamimidamido-1-[[(2S)-1-[[(2S)-5-carbamimidamido-1-[[(2S)-3-carboxy-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-4-carboxy-1-[[(2S)-1-[[2-(carboxymethylamino)-2-oxoethyl]amino]-1-oxopropan-2-yl]amino]-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopentan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-6-oxohexyl]amino]-2-(hexadecanoylamino)-5-oxopentanoic acid Chemical compound CCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCCC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)Cc1c[nH]cn1)[C@@H](C)O)[C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)NCC(=O)NCC(O)=O)C(O)=O YEKUUBPJRPXMBM-PTCFZACGSA-N 0.000 description 1
- WDBIPGHUEJEKTC-VWQPKTIXSA-N (2S,3R,4R,5S,6R)-2-[3-[[4-[[(1R,5S)-3-bicyclo[3.1.0]hexanyl]oxy]phenyl]methyl]-4-chlorophenyl]-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound OC[C@H]1O[C@H]([C@H](O)[C@@H](O)[C@@H]1O)c1ccc(Cl)c(Cc2ccc(OC3C[C@@H]4C[C@@H]4C3)cc2)c1 WDBIPGHUEJEKTC-VWQPKTIXSA-N 0.000 description 1
- ZWASRJHIEFYJGL-BFUOFWGJSA-N (2r)-1,1,1-trifluoro-2-[3-[(2r)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl]sulfonylphenyl]propan-2-ol Chemical compound C([C@H]1C)N(C=2C(=CC(F)=CC=2)C(F)(F)F)CCN1S(=O)(=O)C1=CC=CC([C@@](C)(O)C(F)(F)F)=C1 ZWASRJHIEFYJGL-BFUOFWGJSA-N 0.000 description 1
- REITVGIIZHFVGU-LJQANCHMSA-N (2r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[(2-methylpropan-2-yl)oxy]propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@H](COC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 REITVGIIZHFVGU-LJQANCHMSA-N 0.000 description 1
- KLBPUVPNPAJWHZ-UMSFTDKQSA-N (2r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanylpropanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)SC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 KLBPUVPNPAJWHZ-UMSFTDKQSA-N 0.000 description 1
- QWXZOFZKSQXPDC-LLVKDONJSA-N (2r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@H](C)C(O)=O)C3=CC=CC=C3C2=C1 QWXZOFZKSQXPDC-LLVKDONJSA-N 0.000 description 1
- MSFZPBXAGPYVFD-NFBCFJMWSA-N (2r)-2-amino-3-[1-[3-[2-[2-[2-[4-[[(5s)-5,6-diamino-6-oxohexyl]amino]butylamino]-2-oxoethoxy]ethoxy]ethylamino]-3-oxopropyl]-2,5-dioxopyrrolidin-3-yl]sulfanylpropanoic acid Chemical compound NC(=O)[C@@H](N)CCCCNCCCCNC(=O)COCCOCCNC(=O)CCN1C(=O)CC(SC[C@H](N)C(O)=O)C1=O MSFZPBXAGPYVFD-NFBCFJMWSA-N 0.000 description 1
- ZPGDWQNBZYOZTI-SFHVURJKSA-N (2s)-1-(9h-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 ZPGDWQNBZYOZTI-SFHVURJKSA-N 0.000 description 1
- OJQLGILETRTDGQ-IRXDYDNUSA-N (2s)-1-[3-[2-[3-[[(5s)-5-amino-5-carboxypentyl]amino]propoxy]ethoxy]propyl]pyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H](N)CCCCNCCCOCCOCCCN1CCC[C@H]1C(O)=O OJQLGILETRTDGQ-IRXDYDNUSA-N 0.000 description 1
- REITVGIIZHFVGU-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[(2-methylpropan-2-yl)oxy]propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](COC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 REITVGIIZHFVGU-IBGZPJMESA-N 0.000 description 1
- ADOHASQZJSJZBT-SANMLTNESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[1-[(2-methylpropan-2-yl)oxycarbonyl]indol-3-yl]propanoic acid Chemical compound C12=CC=CC=C2N(C(=O)OC(C)(C)C)C=C1C[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 ADOHASQZJSJZBT-SANMLTNESA-N 0.000 description 1
- JAUKCFULLJFBFN-VWLOTQADSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[4-[(2-methylpropan-2-yl)oxy]phenyl]propanoic acid Chemical compound C1=CC(OC(C)(C)C)=CC=C1C[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 JAUKCFULLJFBFN-VWLOTQADSA-N 0.000 description 1
- UGNIYGNGCNXHTR-SFHVURJKSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-methylbutanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](C(C)C)C(O)=O)C3=CC=CC=C3C2=C1 UGNIYGNGCNXHTR-SFHVURJKSA-N 0.000 description 1
- FODJWPHPWBKDON-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-[(2-methylpropan-2-yl)oxy]-4-oxobutanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 FODJWPHPWBKDON-IBGZPJMESA-N 0.000 description 1
- CBPJQFCAFFNICX-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-methylpentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CC(C)C)C(O)=O)C3=CC=CC=C3C2=C1 CBPJQFCAFFNICX-IBGZPJMESA-N 0.000 description 1
- BUBGAUHBELNDEW-SFHVURJKSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-methylsulfanylbutanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCSC)C(O)=O)C3=CC=CC=C3C2=C1 BUBGAUHBELNDEW-SFHVURJKSA-N 0.000 description 1
- UMRUUWFGLGNQLI-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 UMRUUWFGLGNQLI-QFIPXVFZSA-N 0.000 description 1
- QWXZOFZKSQXPDC-NSHDSACASA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](C)C(O)=O)C3=CC=CC=C3C2=C1 QWXZOFZKSQXPDC-NSHDSACASA-N 0.000 description 1
- HNICLNKVURBTKV-NDEPHWFRSA-N (2s)-5-[[amino-[(2,2,4,6,7-pentamethyl-3h-1-benzofuran-5-yl)sulfonylamino]methylidene]amino]-2-(9h-fluoren-9-ylmethoxycarbonylamino)pentanoic acid Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)N[C@H](C(O)=O)CCCN=C(N)NS(=O)(=O)C1=C(C)C(C)=C2OC(C)(C)CC2=C1C HNICLNKVURBTKV-NDEPHWFRSA-N 0.000 description 1
- XFJAMQQAAMJFGB-ZQGJOIPISA-N (2s,3r,4r,5s,6r)-2-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-ethylphenyl]-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound C1=C(CC=2C=C3OCCOC3=CC=2)C(CC)=CC=C1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O XFJAMQQAAMJFGB-ZQGJOIPISA-N 0.000 description 1
- QKDRXGFQVGOQKS-CRSSMBPESA-N (2s,3r,4r,5s,6r)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methylsulfanyloxane-3,4,5-triol Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](SC)O2)O)=CC=C1Cl QKDRXGFQVGOQKS-CRSSMBPESA-N 0.000 description 1
- BTCRKOKVYTVOLU-SJSRKZJXSA-N (2s,3r,4r,5s,6r)-2-[4-chloro-3-[[4-(2-cyclopropyloxyethoxy)phenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(Cl)C(CC=2C=CC(OCCOC3CC3)=CC=2)=C1 BTCRKOKVYTVOLU-SJSRKZJXSA-N 0.000 description 1
- QXVFEIPAZSXRGM-DJJJIMSYSA-N (2s,3s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-methylpentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H]([C@@H](C)CC)C(O)=O)C3=CC=CC=C3C2=C1 QXVFEIPAZSXRGM-DJJJIMSYSA-N 0.000 description 1
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- JSYGLDMGERSRPC-FQUUOJAGSA-N (2s,4s)-4-fluoro-1-[2-[[(1r,3s)-3-(1,2,4-triazol-1-ylmethyl)cyclopentyl]amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound C1[C@@H](F)C[C@@H](C#N)N1C(=O)CN[C@H]1C[C@@H](CN2N=CN=C2)CC1 JSYGLDMGERSRPC-FQUUOJAGSA-N 0.000 description 1
- GCERFBKFVDLDKD-NRYJBHHQSA-N (3r)-3-amino-1-[3-(trifluoromethyl)-6,8-dihydro-5h-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one;3-(diaminomethylidene)-1,1-dimethylguanidine;phosphoric acid;hydrochloride Chemical compound Cl.OP(O)(O)=O.CN(C)C(=N)N=C(N)N.C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F GCERFBKFVDLDKD-NRYJBHHQSA-N 0.000 description 1
- TXNPQZGSVXLGGP-MMTVBGGISA-N (6s)-6-(2-hydroxy-2-methylpropyl)-3-[(1s)-1-[4-(1-methyl-2-oxopyridin-4-yl)phenyl]ethyl]-6-phenyl-1,3-oxazinan-2-one Chemical compound C1([C@@]2(CC(C)(C)O)CCN(C(O2)=O)[C@@H](C)C=2C=CC(=CC=2)C2=CC(=O)N(C)C=C2)=CC=CC=C1 TXNPQZGSVXLGGP-MMTVBGGISA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- DHBXNPKRAUYBTH-UHFFFAOYSA-N 1,1-ethanedithiol Chemical compound CC(S)S DHBXNPKRAUYBTH-UHFFFAOYSA-N 0.000 description 1
- OAAZMUGLOXGVNH-UHFFFAOYSA-N 1-(3-hydroxyazetidin-1-yl)-2-(6-hydroxy-2-phenyl-2-adamantyl)ethanone Chemical compound C1C(O)CN1C(=O)CC1(C=2C=CC=CC=2)C2CC(C3O)CC1CC3C2 OAAZMUGLOXGVNH-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- DFPYXQYWILNVAU-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1.C1=CC=C2N(O)N=NC2=C1 DFPYXQYWILNVAU-UHFFFAOYSA-N 0.000 description 1
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 description 1
- HOZZVEPRYYCBTO-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)-2-methylpropanoic acid Chemical compound C1=CC=C2C(COC(=O)NC(C)(C)C(O)=O)C3=CC=CC=C3C2=C1 HOZZVEPRYYCBTO-UHFFFAOYSA-N 0.000 description 1
- NDKDFTQNXLHCGO-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)acetic acid Chemical compound C1=CC=C2C(COC(=O)NCC(=O)O)C3=CC=CC=C3C2=C1 NDKDFTQNXLHCGO-UHFFFAOYSA-N 0.000 description 1
- NFTMKHWBOINJGM-UHFFFAOYSA-N 2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]-4-[[4-(tetrazol-1-yl)phenoxy]methyl]-1,3-thiazole Chemical compound N1=CC(CC)=CN=C1N1CCC(C=2SC=C(COC=3C=CC(=CC=3)N3N=NN=C3)N=2)CC1 NFTMKHWBOINJGM-UHFFFAOYSA-N 0.000 description 1
- GXALXAKNHIROPE-UHFFFAOYSA-N 2-[4-[4-[5-[[6-(trifluoromethyl)pyridin-3-yl]amino]pyridin-2-yl]phenyl]cyclohexyl]acetic acid Chemical compound C1CC(CC(=O)O)CCC1C1=CC=C(C=2N=CC(NC=3C=NC(=CC=3)C(F)(F)F)=CC=2)C=C1 GXALXAKNHIROPE-UHFFFAOYSA-N 0.000 description 1
- AYKLXGCULGWUJX-UHFFFAOYSA-N 2-[5-chloro-2-[[1-[(3,4-difluorophenyl)methyl]-4-[(4-methylsulfonylphenyl)methyl]pyrrole-2-carbonyl]amino]-1,3-thiazol-4-yl]acetic acid Chemical compound C1=CC(S(=O)(=O)C)=CC=C1CC1=CN(CC=2C=C(F)C(F)=CC=2)C(C(=O)NC=2SC(Cl)=C(CC(O)=O)N=2)=C1 AYKLXGCULGWUJX-UHFFFAOYSA-N 0.000 description 1
- HPGJSAAUJGAMLV-UHFFFAOYSA-N 2-[[2-[[cyclohexyl-(4-propoxycyclohexyl)carbamoyl]amino]-1,3-thiazol-5-yl]sulfanyl]acetic acid Chemical compound C1CC(OCCC)CCC1N(C(=O)NC=1SC(SCC(O)=O)=CN=1)C1CCCCC1 HPGJSAAUJGAMLV-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- ZJSQZQMVXKZAGW-UHFFFAOYSA-N 2H-benzotriazol-4-ol hydrate Chemical compound O.OC1=CC=CC2=C1N=NN2 ZJSQZQMVXKZAGW-UHFFFAOYSA-N 0.000 description 1
- APIXJSLKIYYUKG-UHFFFAOYSA-N 3 Isobutyl 1 methylxanthine Chemical compound O=C1N(C)C(=O)N(CC(C)C)C2=C1N=CN2 APIXJSLKIYYUKG-UHFFFAOYSA-N 0.000 description 1
- FODHWOBAQBTTFS-UHFFFAOYSA-N 3-[4-[2-(2-methylphenyl)ethynyl]phenyl]propanoic acid Chemical compound CC1=CC=CC=C1C#CC1=CC=C(CCC(O)=O)C=C1 FODHWOBAQBTTFS-UHFFFAOYSA-N 0.000 description 1
- OCNBSSLDAIWTKS-UHFFFAOYSA-N 3-[[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]methyl]-n,n-bis(cyclopropylmethyl)-8-methylquinolin-2-amine Chemical compound C1CC1CN(CC1CC1)C=1N=C2C(C)=CC=CC2=CC=1CN(C1=NN(C)N=N1)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 OCNBSSLDAIWTKS-UHFFFAOYSA-N 0.000 description 1
- XABCFXXGZPWJQP-UHFFFAOYSA-N 3-aminoadipic acid Chemical compound OC(=O)CC(N)CCC(O)=O XABCFXXGZPWJQP-UHFFFAOYSA-N 0.000 description 1
- YDNMHDRXNOHCJH-UHFFFAOYSA-N 3-aminopyrrolidine-2,5-dione Chemical compound NC1CC(=O)NC1=O YDNMHDRXNOHCJH-UHFFFAOYSA-N 0.000 description 1
- SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical class COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 description 1
- XWBXJBSVYVJAMZ-UHFFFAOYSA-N 4-[4-(2-adamantylcarbamoyl)-5-tert-butylpyrazol-1-yl]benzoic acid Chemical compound CC(C)(C)C1=C(C(=O)NC2C3CC4CC(C3)CC2C4)C=NN1C1=CC=C(C(O)=O)C=C1 XWBXJBSVYVJAMZ-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 1
- 102000006902 5-HT2C Serotonin Receptor Human genes 0.000 description 1
- 108010072553 5-HT2C Serotonin Receptor Proteins 0.000 description 1
- AYJRTVVIBJSSKN-UHFFFAOYSA-N 5-[4-[[6-(4-methylsulfonylphenyl)pyridin-3-yl]oxymethyl]piperidin-1-yl]-3-propan-2-yl-1,2,4-oxadiazole Chemical compound CC(C)C1=NOC(N2CCC(COC=3C=NC(=CC=3)C=3C=CC(=CC=3)S(C)(=O)=O)CC2)=N1 AYJRTVVIBJSSKN-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 208000004611 Abdominal Obesity Diseases 0.000 description 1
- 208000022309 Alcoholic Liver disease Diseases 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 101100460776 Arabidopsis thaliana NPY2 gene Proteins 0.000 description 1
- 101100460788 Arabidopsis thaliana NPY5 gene Proteins 0.000 description 1
- KLKHFFMNGWULBN-VKHMYHEASA-N Asn-Gly Chemical group NC(=O)C[C@H](N)C(=O)NCC(O)=O KLKHFFMNGWULBN-VKHMYHEASA-N 0.000 description 1
- JHFNSBBHKSZXKB-VKHMYHEASA-N Asp-Gly Chemical group OC(=O)C[C@H](N)C(=O)NCC(O)=O JHFNSBBHKSZXKB-VKHMYHEASA-N 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- PTQXTEKSNBVPQJ-UHFFFAOYSA-N Avasimibe Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1CC(=O)NS(=O)(=O)OC1=C(C(C)C)C=CC=C1C(C)C PTQXTEKSNBVPQJ-UHFFFAOYSA-N 0.000 description 1
- 239000005485 Azilsartan Substances 0.000 description 1
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 230000005653 Brownian motion process Effects 0.000 description 1
- 102100031151 C-C chemokine receptor type 2 Human genes 0.000 description 1
- 101710149815 C-C chemokine receptor type 2 Proteins 0.000 description 1
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- 239000002080 C09CA02 - Eprosartan Substances 0.000 description 1
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 1
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 1
- 239000002081 C09CA05 - Tasosartan Substances 0.000 description 1
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 1
- 239000005537 C09CA07 - Telmisartan Substances 0.000 description 1
- WEDIKSVWBUKTRA-WTKGVUNUSA-N CC[C@H](C)[C@H](NC(=O)CN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H]1CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc3c[nH]cn3)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc3ccccc3)C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](Cc3c[nH]cn3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc3ccc(O)cc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC2=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)NC1=O)[C@@H](C)O)[C@@H](C)CC Chemical compound CC[C@H](C)[C@H](NC(=O)CN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H]1CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc3c[nH]cn3)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc3ccccc3)C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](Cc3c[nH]cn3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc3ccc(O)cc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC2=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)NC1=O)[C@@H](C)O)[C@@H](C)CC WEDIKSVWBUKTRA-WTKGVUNUSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- XTNGUQKDFGDXSJ-ZXGKGEBGSA-N Canagliflozin Chemical compound CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 XTNGUQKDFGDXSJ-ZXGKGEBGSA-N 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- 206010065941 Central obesity Diseases 0.000 description 1
- 229920001268 Cholestyramine Polymers 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 102100036869 Diacylglycerol O-acyltransferase 1 Human genes 0.000 description 1
- 108050004099 Diacylglycerol O-acyltransferase 1 Proteins 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 206010014486 Elevated triglycerides Diseases 0.000 description 1
- MCIACXAZCBVDEE-CUUWFGFTSA-N Ertugliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@@]23O[C@@](CO)(CO2)[C@@H](O)[C@H](O)[C@H]3O)=CC=C1Cl MCIACXAZCBVDEE-CUUWFGFTSA-N 0.000 description 1
- 108010043222 Exubera Proteins 0.000 description 1
- 102100026148 Free fatty acid receptor 1 Human genes 0.000 description 1
- 102000027487 Fructose-Bisphosphatase Human genes 0.000 description 1
- 108010017464 Fructose-Bisphosphatase Proteins 0.000 description 1
- 229940100607 GPR119 agonist Drugs 0.000 description 1
- 108091007911 GSKs Proteins 0.000 description 1
- ZWPRRQZNBDYKLH-VIFPVBQESA-N Gemigliptin Chemical compound C([C@@H](N)CC(=O)N1CC2=C(C(=NC(=N2)C(F)(F)F)C(F)(F)F)CC1)N1CC(F)(F)CCC1=O ZWPRRQZNBDYKLH-VIFPVBQESA-N 0.000 description 1
- 208000034826 Genetic Predisposition to Disease Diseases 0.000 description 1
- 101800001586 Ghrelin Proteins 0.000 description 1
- 102400000442 Ghrelin-28 Human genes 0.000 description 1
- 102400000322 Glucagon-like peptide 1 Human genes 0.000 description 1
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 1
- 102000030595 Glucokinase Human genes 0.000 description 1
- 108010021582 Glucokinase Proteins 0.000 description 1
- 102000003638 Glucose-6-Phosphatase Human genes 0.000 description 1
- 108010086800 Glucose-6-Phosphatase Proteins 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 102000007390 Glycogen Phosphorylase Human genes 0.000 description 1
- 108010046163 Glycogen Phosphorylase Proteins 0.000 description 1
- 102000004103 Glycogen Synthase Kinases Human genes 0.000 description 1
- 102100030488 HEAT repeat-containing protein 6 Human genes 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- 102100035043 Histone-lysine N-methyltransferase EHMT1 Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000912510 Homo sapiens Free fatty acid receptor 1 Proteins 0.000 description 1
- 101000990566 Homo sapiens HEAT repeat-containing protein 6 Proteins 0.000 description 1
- 101000801684 Homo sapiens Phospholipid-transporting ATPase ABCA1 Proteins 0.000 description 1
- 101001098868 Homo sapiens Proprotein convertase subtilisin/kexin type 9 Proteins 0.000 description 1
- 108010090613 Human Regular Insulin Proteins 0.000 description 1
- 102000013266 Human Regular Insulin Human genes 0.000 description 1
- 102100021102 Hyaluronidase PH-20 Human genes 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 229940077672 Ileal bile acid transport inhibitor Drugs 0.000 description 1
- 206010021518 Impaired gastric emptying Diseases 0.000 description 1
- 108010089308 Insulin Detemir Proteins 0.000 description 1
- FYZPCMFQCNBYCY-WIWKJPBBSA-N Insulin degludec Chemical compound CC[C@H](C)[C@H](NC(=O)CN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H]1CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc3c[nH]cn3)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc3ccccc3)C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](Cc3c[nH]cn3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc3ccc(O)cc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC2=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H]([C@@H](C)O)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC(O)=O)C(O)=O)C(O)=O)NC1=O)[C@@H](C)O)[C@@H](C)CC FYZPCMFQCNBYCY-WIWKJPBBSA-N 0.000 description 1
- 229940127019 JNJ-64565111 Drugs 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- 238000008214 LDL Cholesterol Methods 0.000 description 1
- WHSOLWOTCHFFBK-ZQGJOIPISA-N Luseogliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)S2)O)=C(OC)C=C1C WHSOLWOTCHFFBK-ZQGJOIPISA-N 0.000 description 1
- 206010054805 Macroangiopathy Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 description 1
- IRLWJILLXJGJTD-UHFFFAOYSA-N Muraglitazar Chemical compound C1=CC(OC)=CC=C1OC(=O)N(CC(O)=O)CC(C=C1)=CC=C1OCCC1=C(C)OC(C=2C=CC=CC=2)=N1 IRLWJILLXJGJTD-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000023178 Musculoskeletal disease Diseases 0.000 description 1
- 101150111774 NPY5R gene Proteins 0.000 description 1
- 238000011887 Necropsy Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 108010036875 ORMD-0801 Proteins 0.000 description 1
- 239000005480 Olmesartan Substances 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- 102000018886 Pancreatic Polypeptide Human genes 0.000 description 1
- 108700020479 Pancreatic hormone Proteins 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 102100038824 Peroxisome proliferator-activated receptor delta Human genes 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 108010076181 Proinsulin Proteins 0.000 description 1
- 102100038955 Proprotein convertase subtilisin/kexin type 9 Human genes 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 230000010799 Receptor Interactions Effects 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- 101150055528 SPAM1 gene Proteins 0.000 description 1
- DLSWIYLPEUIQAV-UHFFFAOYSA-N Semaglutide Chemical compound CCC(C)C(NC(=O)C(Cc1ccccc1)NC(=O)C(CCC(O)=O)NC(=O)C(CCCCNC(=O)COCCOCCNC(=O)COCCOCCNC(=O)CCC(NC(=O)CCCCCCCCCCCCCCCCC(O)=O)C(O)=O)NC(=O)C(C)NC(=O)C(C)NC(=O)C(CCC(N)=O)NC(=O)CNC(=O)C(CCC(O)=O)NC(=O)C(CC(C)C)NC(=O)C(Cc1ccc(O)cc1)NC(=O)C(CO)NC(=O)C(CO)NC(=O)C(NC(=O)C(CC(O)=O)NC(=O)C(CO)NC(=O)C(NC(=O)C(Cc1ccccc1)NC(=O)C(NC(=O)CNC(=O)C(CCC(O)=O)NC(=O)C(C)(C)NC(=O)C(N)Cc1cnc[nH]1)C(C)O)C(C)O)C(C)C)C(=O)NC(C)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)NC(CC(C)C)C(=O)NC(C(C)C)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CCCNC(N)=N)C(=O)NCC(O)=O DLSWIYLPEUIQAV-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 206010042618 Surgical procedure repeated Diseases 0.000 description 1
- 229940127105 TT-401 Drugs 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 102100033121 Transcription factor 21 Human genes 0.000 description 1
- 101710119687 Transcription factor 21 Proteins 0.000 description 1
- 102000008316 Type 4 Melanocortin Receptor Human genes 0.000 description 1
- 108010021436 Type 4 Melanocortin Receptor Proteins 0.000 description 1
- 101710204865 Tyrosine-protein phosphatase 1 Proteins 0.000 description 1
- FZNCGRZWXLXZSZ-CIQUZCHMSA-N Voglibose Chemical compound OCC(CO)N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O FZNCGRZWXLXZSZ-CIQUZCHMSA-N 0.000 description 1
- 239000003875 Wang resin Substances 0.000 description 1
- 102400000752 Xenin Human genes 0.000 description 1
- NERFNHBZJXXFGY-UHFFFAOYSA-N [4-[(4-methylphenyl)methoxy]phenyl]methanol Chemical compound C1=CC(C)=CC=C1COC1=CC=C(CO)C=C1 NERFNHBZJXXFGY-UHFFFAOYSA-N 0.000 description 1
- 229960002632 acarbose Drugs 0.000 description 1
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 108010076089 accutase Proteins 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 210000004404 adrenal cortex Anatomy 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 239000000670 adrenergic alpha-2 receptor antagonist Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229940078883 afrezza Drugs 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229960004733 albiglutide Drugs 0.000 description 1
- OGWAVGNOAMXIIM-UHFFFAOYSA-N albiglutide Chemical compound O=C(O)C(NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)CNC(=O)C(NC(=O)CNC(=O)C(N)CC=1(N=CNC=1))CCC(=O)O)C(O)C)CC2(=CC=CC=C2))C(O)C)CO)CC(=O)O)C(C)C)CO)CO)CC3(=CC=C(O)C=C3))CC(C)C)CCC(=O)O)CCC(=O)N)C)C)CCCCN)CCC(=O)O)CC4(=CC=CC=C4))C(CC)C)C)CC=6(C5(=C(C=CC=C5)NC=6)))CC(C)C)C(C)C)CCCCN)CCCNC(=N)N OGWAVGNOAMXIIM-UHFFFAOYSA-N 0.000 description 1
- 229960001667 alogliptin Drugs 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- 102000030484 alpha-2 Adrenergic Receptor Human genes 0.000 description 1
- 108020004101 alpha-2 Adrenergic Receptor Proteins 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229940000806 amaryl Drugs 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000003941 amyloidogenesis Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 229950009977 anagliptin Drugs 0.000 description 1
- LDXYBEHACFJIEL-HNNXBMFYSA-N anagliptin Chemical compound C=1N2N=C(C)C=C2N=CC=1C(=O)NCC(C)(C)NCC(=O)N1CCC[C@H]1C#N LDXYBEHACFJIEL-HNNXBMFYSA-N 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 230000006909 anti-apoptosis Effects 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 229940125708 antidiabetic agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000003705 antithrombocytic agent Substances 0.000 description 1
- 229940112930 apidra Drugs 0.000 description 1
- RCHHVVGSTHAVPF-ZPHPLDECSA-N apidra Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3N=CNC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CNC=N1 RCHHVVGSTHAVPF-ZPHPLDECSA-N 0.000 description 1
- 208000008784 apnea Diseases 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 239000002830 appetite depressant Substances 0.000 description 1
- 108010047857 aspartylglycine Proteins 0.000 description 1
- 230000000923 atherogenic effect Effects 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- 229950010046 avasimibe Drugs 0.000 description 1
- 229960002731 azilsartan Drugs 0.000 description 1
- KGSXMPPBFPAXLY-UHFFFAOYSA-N azilsartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NOC(=O)N1 KGSXMPPBFPAXLY-UHFFFAOYSA-N 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229950003611 bexagliflozin Drugs 0.000 description 1
- 229960000516 bezafibrate Drugs 0.000 description 1
- IIBYAHWJQTYFKB-UHFFFAOYSA-N bezafibrate Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1CCNC(=O)C1=CC=C(Cl)C=C1 IIBYAHWJQTYFKB-UHFFFAOYSA-N 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- NOJMTMIRQRDZMT-GSPXQYRGSA-N bromocriptine methanesulfonate Chemical compound CS(O)(=O)=O.C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 NOJMTMIRQRDZMT-GSPXQYRGSA-N 0.000 description 1
- 238000005537 brownian motion Methods 0.000 description 1
- 229960004111 buformin Drugs 0.000 description 1
- XSEUMFJMFFMCIU-UHFFFAOYSA-N buformin Chemical compound CCCC\N=C(/N)N=C(N)N XSEUMFJMFFMCIU-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940014641 bydureon Drugs 0.000 description 1
- 229940084891 byetta Drugs 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229960000932 candesartan Drugs 0.000 description 1
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 description 1
- 230000023852 carbohydrate metabolic process Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000003293 cardioprotective effect Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- WGEWUYACXPEFPO-AULYBMBSSA-N chembl2016681 Chemical compound C1C[C@@H](NS(=O)(=O)C(C)(C)C)CC[C@@H]1C(=O)NC1=CC=C(C(F)(F)F)C=N1 WGEWUYACXPEFPO-AULYBMBSSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000001906 cholesterol absorption Effects 0.000 description 1
- 239000003354 cholesterol ester transfer protein inhibitor Substances 0.000 description 1
- ASARMUCNOOHMLO-WLORSUFZSA-L cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2s)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@H](C)OP([O-])(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O ASARMUCNOOHMLO-WLORSUFZSA-L 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 230000001427 coherent effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940121426 cotadutide Drugs 0.000 description 1
- 108091005205 cotadutide Proteins 0.000 description 1
- 230000001517 counterregulatory effect Effects 0.000 description 1
- 229940015838 cycloset Drugs 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- DBOBAIHRZONIPT-GHCHSQRSSA-N decanedioic acid;2,2-dimethyl-3-[3-[3-methyl-4-[[5-propan-2-yl-3-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-1h-pyrazol-4-yl]methyl]phenoxy]propylamino]propanamide Chemical compound OC(=O)CCCCCCCCC(O)=O.C=1C=C(OCCCNCC(C)(C)C(N)=O)C=C(C)C=1CC1=C(C(C)C)NN=C1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.C=1C=C(OCCCNCC(C)(C)C(N)=O)C=C(C)C=1CC1=C(C(C)C)NN=C1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O DBOBAIHRZONIPT-GHCHSQRSSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 229940127257 dual PPAR agonist Drugs 0.000 description 1
- 229940125542 dual agonist Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 229960005175 dulaglutide Drugs 0.000 description 1
- 108010005794 dulaglutide Proteins 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 229950004145 efpeglenatide Drugs 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 229960003345 empagliflozin Drugs 0.000 description 1
- OBWASQILIWPZMG-QZMOQZSNSA-N empagliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(Cl)C(CC=2C=CC(O[C@@H]3COCC3)=CC=2)=C1 OBWASQILIWPZMG-QZMOQZSNSA-N 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 210000003158 enteroendocrine cell Anatomy 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229960004563 eprosartan Drugs 0.000 description 1
- OROAFUQRIXKEMV-LDADJPATSA-N eprosartan Chemical compound C=1C=C(C(O)=O)C=CC=1CN1C(CCCC)=NC=C1\C=C(C(O)=O)/CC1=CC=CS1 OROAFUQRIXKEMV-LDADJPATSA-N 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 229940012151 exubera Drugs 0.000 description 1
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 1
- 229950007405 fasiglifam Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229960002297 fenofibrate Drugs 0.000 description 1
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229960002458 gemigliptin Drugs 0.000 description 1
- 208000004104 gestational diabetes Diseases 0.000 description 1
- GNKDKYIHGQKHHM-RJKLHVOGSA-N ghrelin Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)CN)COC(=O)CCCCCCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C1=CC=CC=C1 GNKDKYIHGQKHHM-RJKLHVOGSA-N 0.000 description 1
- 229960004580 glibenclamide Drugs 0.000 description 1
- 229960004346 glimepiride Drugs 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 229960001381 glipizide Drugs 0.000 description 1
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 1
- 230000002039 glucoregulatory effect Effects 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-L glutamate group Chemical group N[C@@H](CCC(=O)[O-])C(=O)[O-] WHUUTDBJXJRKMK-VKHMYHEASA-L 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 102000034345 heterotrimeric G proteins Human genes 0.000 description 1
- 108091006093 heterotrimeric G proteins Proteins 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229940038661 humalog Drugs 0.000 description 1
- 229940103471 humulin Drugs 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 239000005555 hypertensive agent Substances 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229960004717 insulin aspart Drugs 0.000 description 1
- 108010050259 insulin degludec Proteins 0.000 description 1
- 229960003948 insulin detemir Drugs 0.000 description 1
- 108700039926 insulin glulisine Proteins 0.000 description 1
- 230000006362 insulin response pathway Effects 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229940121068 invokana Drugs 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229950000991 ipragliflozin Drugs 0.000 description 1
- AHFWIQIYAXSLBA-RQXATKFSSA-N ipragliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(F)C(CC=2SC3=CC=CC=C3C=2)=C1 AHFWIQIYAXSLBA-RQXATKFSSA-N 0.000 description 1
- 229960002198 irbesartan Drugs 0.000 description 1
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000000741 isoleucyl group Chemical group [H]N([H])C(C(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(=O)O* 0.000 description 1
- 229940103445 janumet Drugs 0.000 description 1
- 229940090473 januvia Drugs 0.000 description 1
- 229940060975 lantus Drugs 0.000 description 1
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940102988 levemir Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 229960005060 lorcaserin Drugs 0.000 description 1
- XTTZERNUQAFMOF-QMMMGPOBSA-N lorcaserin Chemical compound C[C@H]1CNCCC2=CC=C(Cl)C=C12 XTTZERNUQAFMOF-QMMMGPOBSA-N 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229950004397 luseogliflozin Drugs 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 229950004994 meglitinide Drugs 0.000 description 1
- 229950009585 melogliptin Drugs 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 description 1
- 150000002741 methionine derivatives Chemical group 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- 108700008455 metreleptin Proteins 0.000 description 1
- 229960000668 metreleptin Drugs 0.000 description 1
- 229960001110 miglitol Drugs 0.000 description 1
- 244000309715 mini pig Species 0.000 description 1
- 229960003365 mitiglinide Drugs 0.000 description 1
- WPGGHFDDFPHPOB-BBWFWOEESA-N mitiglinide Chemical compound C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)O)C1=CC=CC=C1 WPGGHFDDFPHPOB-BBWFWOEESA-N 0.000 description 1
- 229950001135 muraglitazar Drugs 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- CMWYAOXYQATXSI-UHFFFAOYSA-N n,n-dimethylformamide;piperidine Chemical compound CN(C)C=O.C1CCNCC1 CMWYAOXYQATXSI-UHFFFAOYSA-N 0.000 description 1
- BNPZTRDIESRGTC-IXYVTWBDSA-N n-[2-(dimethylamino)ethyl]-2-methyl-2-[4-[4-[[2-methyl-5-[(2s,3r,4r,5s,6r)-3,4,5-trihydroxy-6-methylsulfanyloxan-2-yl]phenyl]methyl]phenyl]butanoylamino]propanamide Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](SC)O[C@H]1C1=CC=C(C)C(CC=2C=CC(CCCC(=O)NC(C)(C)C(=O)NCCN(C)C)=CC=2)=C1 BNPZTRDIESRGTC-IXYVTWBDSA-N 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 1
- 229960003086 naltrexone Drugs 0.000 description 1
- 229960000698 nateglinide Drugs 0.000 description 1
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 description 1
- 230000009707 neogenesis Effects 0.000 description 1
- 230000001607 nephroprotective effect Effects 0.000 description 1
- 229940117337 nesina Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000001019 normoglycemic effect Effects 0.000 description 1
- VOMXSOIBEJBQNF-UTTRGDHVSA-N novorapid Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CS)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1.C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 VOMXSOIBEJBQNF-UTTRGDHVSA-N 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 229960005117 olmesartan Drugs 0.000 description 1
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 1
- 229950000074 omarigliptin Drugs 0.000 description 1
- 229940001450 onglyza Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 1
- 229960001243 orlistat Drugs 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000002571 pancreatic alpha cell Anatomy 0.000 description 1
- 239000011087 paperboard Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 108091008765 peroxisome proliferator-activated receptors β/δ Proteins 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003243 phenformin Drugs 0.000 description 1
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229960003562 phentermine Drugs 0.000 description 1
- 229930029653 phosphoenolpyruvate Natural products 0.000 description 1
- DTBNBXWJWCWCIK-UHFFFAOYSA-N phosphoenolpyruvic acid Chemical compound OC(=O)C(=C)OP(O)(O)=O DTBNBXWJWCWCIK-UHFFFAOYSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 108700002854 polyethylene glycol(B1)- insulin Proteins 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000029537 positive regulation of insulin secretion Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- WPDCHTSXOPUOII-UHFFFAOYSA-N propan-2-yl 4-[5-methoxy-6-[(2-methyl-6-methylsulfonylpyridin-3-yl)amino]pyrimidin-4-yl]oxypiperidine-1-carboxylate Chemical compound N1=CN=C(OC2CCN(CC2)C(=O)OC(C)C)C(OC)=C1NC1=CC=C(S(C)(=O)=O)N=C1C WPDCHTSXOPUOII-UHFFFAOYSA-N 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 108700027806 rGLP-1 Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000003979 response to food Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- XMSXOLDPMGMWTH-UHFFFAOYSA-N rivoglitazone Chemical compound CN1C2=CC(OC)=CC=C2N=C1COC(C=C1)=CC=C1CC1SC(=O)NC1=O XMSXOLDPMGMWTH-UHFFFAOYSA-N 0.000 description 1
- 229950010764 rivoglitazone Drugs 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 229960004937 saxagliptin Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 108010060325 semaglutide Proteins 0.000 description 1
- 229950011186 semaglutide Drugs 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229940126842 sergliflozin Drugs 0.000 description 1
- HFLCZNNDZKKXCS-OUUBHVDSSA-N sergliflozin Chemical compound C1=CC(OC)=CC=C1CC1=CC=CC=C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HFLCZNNDZKKXCS-OUUBHVDSSA-N 0.000 description 1
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 1
- 229960004425 sibutramine Drugs 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 229960004034 sitagliptin Drugs 0.000 description 1
- 230000007958 sleep Effects 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940087562 sodium acetate trihydrate Drugs 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 238000013097 stability assessment Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 208000023516 stroke disease Diseases 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 229960000651 tasosartan Drugs 0.000 description 1
- ADXGNEYLLLSOAR-UHFFFAOYSA-N tasosartan Chemical compound C12=NC(C)=NC(C)=C2CCC(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 ADXGNEYLLLSOAR-UHFFFAOYSA-N 0.000 description 1
- WRGVLTAWMNZWGT-VQSPYGJZSA-N taspoglutide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NC(C)(C)C(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)C(C)(C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 WRGVLTAWMNZWGT-VQSPYGJZSA-N 0.000 description 1
- 108010048573 taspoglutide Proteins 0.000 description 1
- 229950007151 taspoglutide Drugs 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- 229950000034 teneligliptin Drugs 0.000 description 1
- WGRQANOPCQRCME-PMACEKPBSA-N teneligliptin Chemical compound O=C([C@H]1NC[C@H](C1)N1CCN(CC1)C1=CC(=NN1C=1C=CC=CC=1)C)N1CCSC1 WGRQANOPCQRCME-PMACEKPBSA-N 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- CXGTZJYQWSUFET-IBGZPJMESA-N tesaglitazar Chemical compound C1=CC(C[C@H](OCC)C(O)=O)=CC=C1OCCC1=CC=C(OS(C)(=O)=O)C=C1 CXGTZJYQWSUFET-IBGZPJMESA-N 0.000 description 1
- 229950004704 tesaglitazar Drugs 0.000 description 1
- VCVWXKKWDOJNIT-ZOMKSWQUSA-N tesofensine Chemical compound C1([C@H]2C[C@@H]3CC[C@@H](N3C)[C@@H]2COCC)=CC=C(Cl)C(Cl)=C1 VCVWXKKWDOJNIT-ZOMKSWQUSA-N 0.000 description 1
- 229950009970 tesofensine Drugs 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000035924 thermogenesis Effects 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- BTSOGEDATSQOAF-SMAAHMJQSA-N tirzepatide Chemical compound CC[C@H](C)[C@@H](C(N[C@@H](C)C(N[C@@H](CCC(N)=O)C(N[C@@H](CCCCNC(COCCOCCNC(COCCOCCNC(CC[C@H](C(O)=O)NC(CCCCCCCCCCCCCCCCCCC(O)=O)=O)=O)=O)=O)C(N[C@@H](C)C(N[C@@H](CC1=CC=CC=C1)C(N[C@@H](C(C)C)C(N[C@@H](CCC(N)=O)C(N[C@@H](CC1=CNC2=C1C=CC=C2)C(N[C@@H](CC(C)C)C(N[C@@H]([C@@H](C)CC)C(N[C@@H](C)C(NCC(NCC(N(CCC1)[C@@H]1C(N[C@@H](CO)C(N[C@@H](CO)C(NCC(N[C@@H](C)C(N(CCC1)[C@@H]1C(N(CCC1)[C@@H]1C(N(CCC1)[C@@H]1C(N[C@@H](CO)C(N)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)NC([C@H](CCCCN)NC([C@H](CC(O)=O)NC([C@H](CC(C)C)NC(C(C)(C)NC([C@H]([C@@H](C)CC)NC([C@H](CO)NC([C@H](CC(C=C1)=CC=C1O)NC([C@H](CC(O)=O)NC([C@H](CO)NC([C@H]([C@@H](C)O)NC([C@H](CC1=CC=CC=C1)NC([C@H]([C@@H](C)O)NC(CNC([C@H](CCC(O)=O)NC(C(C)(C)NC([C@H](CC(C=C1)=CC=C1O)N)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O BTSOGEDATSQOAF-SMAAHMJQSA-N 0.000 description 1
- 229950006667 tofogliflozin Drugs 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- CMSGWTNRGKRWGS-NQIIRXRSSA-N torcetrapib Chemical compound COC(=O)N([C@H]1C[C@@H](CC)N(C2=CC=C(C=C21)C(F)(F)F)C(=O)OCC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 CMSGWTNRGKRWGS-NQIIRXRSSA-N 0.000 description 1
- 229950004514 torcetrapib Drugs 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 229940049667 tradjenta Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 229950010728 trelagliptin Drugs 0.000 description 1
- IWYJYHUNXVAVAA-OAHLLOKOSA-N trelagliptin Chemical compound C=1C(F)=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 IWYJYHUNXVAVAA-OAHLLOKOSA-N 0.000 description 1
- 239000013559 triple agonist Substances 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- WUJVPODXELZABP-FWJXURDUSA-N trodusquemine Chemical compound C([C@@H]1C[C@H]2O)[C@@H](NCCCNCCCCNCCCN)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CC[C@H](C(C)C)OS(O)(=O)=O)[C@@]2(C)CC1 WUJVPODXELZABP-FWJXURDUSA-N 0.000 description 1
- 229950004499 trodusquemine Drugs 0.000 description 1
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
- 229960001641 troglitazone Drugs 0.000 description 1
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 1
- 239000013026 undiluted sample Substances 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 229950006508 velneperit Drugs 0.000 description 1
- 229940007428 victoza Drugs 0.000 description 1
- 229960001729 voglibose Drugs 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 229940124024 weight reducing agent Drugs 0.000 description 1
- 239000013585 weight reducing agent Substances 0.000 description 1
- IDHVLSACPFUBDY-QCDLPZBNSA-N xenin Chemical compound C([C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CN=CN1 IDHVLSACPFUBDY-QCDLPZBNSA-N 0.000 description 1
- 108010006643 xenin 25 Proteins 0.000 description 1
- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 description 1
- 229960002911 zonisamide Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/2278—Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/26—Glucagons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/57563—Vasoactive intestinal peptide [VIP]; Related peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/605—Glucagons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to new compounds which are trigonal GLP-1 / glucagon / GIP receptor agonists and their medical use, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as for reduction of excess food intake.
- the compounds of the invention are structurally derived from exendin-4 and show high solubility and stability under acidic conditions in the presence of antimicrobial preservatives like m-cresol or phenol which makes them especially suited for combinations with other antidiabetic compounds.
- GLP-1 (7-36)-amide The amino acid sequence of GLP-1 (7-36)-amide is shown as SEQ ID NO: 1. HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH 2
- Liraglutide is a marketed chemically modified GLP-1 analog in which, among other modifications, a fatty acid is linked to a lysine in position 20 leading to a prolonged duration of action ( Drucker et al, Nat. Rev. Drug Disc. 2010, 9, 267-268 ; Buse et al., Lancet 2009, 374, 39-47 ).
- Liraglutide is shown as SEQ ID NO: 2.
- Glucagon is a 29-amino acid peptide which is released into the bloodstream when circulating glucose is low. Glucagon's amino acid sequence is shown as SEQ ID NO: 3. HSQGTFTSDYSKYLDSRRAQDFVQWLMNT-OH
- glucagon During hypoglycemia, when blood glucose levels drop below normal, glucagon signals the liver to break down glycogen and release glucose, causing an increase of blood glucose levels to reach a normal level. Recent publications suggest that glucagon has in addition beneficial effects on reduction of body fat mass, reduction of food intake, and increase of energy expenditure ( Heppner et al., Physiology & Behavior 2010, 100, 545-548 ).
- GIP glucose-dependent insulinotropic polypeptide
- GIP and GLP-1 are the two gut enteroendocrine cell-derived hormones accounting for the incretin effect, which accounts for over 70% of the insulin response to an oral glucose challenge ( Baggio et al. Gastroenterology 2007, 132, 2131-2157 ).
- GIP's amino acid sequence is shown as SEQ ID NO: 5. YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ-OH
- Peptides which are based on the structures of GLP-1 or glucagon, and bind and activate the GLP-1, the glucagon and the GIP receptor have been described in patent applications WO 2010/011439 , WO 2010/148089 , WO 2012/088116 , WO 2013/192129 , WO 2013/192130 , WO 2014/049610 and WO 2015/067716 .
- Further trispecific agonists based on exendin-4 have been described in WO 2014/096145 , WO 2015/086731 , WO 2015/086732 , WO 2015/086733 , WO2015/155141 , and PCT/EP2016/063332 .
- the compounds described therein have been shown to lead to improved glycemic control, possible islet and beta-cell preservation and enhanced body weight loss.
- Exendin-4 is a 39 amino acid peptide which is produced by the salivary glands of the Gila monster (Heloderma suspectum. Exendin-4 is an activator of the GLP-1 receptor, whereas it shows low activation of the GIP receptor and does not activate the glucagon receptor (see Table 1). Table 1: Potencies of exendin-4 at human GLP-1, GIP and Glucagon receptors (indicated in pM) at increasing concentrations and measuring the formed cAMP as described in Methods. SEQ ID NO: peptide EC50 hGLP-1 R [pM] EC50 hGIP R [pM] EC50 hGlucagon R [pM] 4 exendin-4 0.4 12500.0 >100000000000
- exendin-4 The amino acid sequence of exendin-4 is shown as SEQ ID NO: 4. HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2
- Exendin-4 shares many of the glucoregulatory actions observed with GLP-1. Clinical and nonclinical studies have shown that exendin-4 has several beneficial antidiabetic properties including a glucose dependent enhancement in insulin synthesis and secretion, glucose dependent suppression of glucagon secretion, slowing down gastric emptying, reduction of food intake and body weight, and an increase in beta-cell mass and markers of beta cell function.
- exendin-4 is resistant to cleavage by dipeptidyl peptidase-4 (DPP4) resulting in a longer half-life and duration of action in vivo ( Eng J., Diabetes, 1996, 45 (Suppl 2):152A (abstract 554 )).
- DPP4 dipeptidyl peptidase-4
- Exendin-4 was also shown to be much more stable towards degradation by neutral endopeptidase (NEP), when compared to GLP-1, glucagon or oxyntomodulin ( Druce et al., Endocrinology, 2009, 150(4), 1712-1722 ). Nevertheless, exendin-4 is chemically labile due to methionine oxidation in position 14 ( Hargrove et al., Regul. Pept., 2007, 141, 113-119 ) as well as deamidation and isomerization of asparagine in position 28 ( WO 2004/035623 ).
- Bloom et al. disclose that peptides which bind and activate both the glucagon and the GLP-1 receptor can be constructed as hybrid molecules from glucagon and exendin-4, where the N-terminal part (e.g. residues 1-14 or 1-24) originates from glucagon and the C-terminal part (e.g. residues 15-39 or 25-39) originates from exendin-4.
- Such peptides comprise glucagon's amino acid motif YSKY in position 10-13.
- Krstenansky et al show the importance of these residues 10-13 of glucagon for its receptor interactions and activation of adenylate cyclase.
- exendin-4 Compared to GLP-1, glucagon and oxyntomodulin, exendin-4 has beneficial physicochemical properties, such as solubility and stability in solution and under physiological conditions (including enzymatic stability towards degradation by enzymes, such as DPP4 or NEP), which results in a longer duration of action in vivo.
- exendin-4 has been shown to be chemically labile due to methionine oxidation in position 14 as well as deamidation and isomerization of asparagine in position 28. Stability might be further improved by substitution of methionine at position 14 and the avoidance of sequences that are known to be prone to degradation via aspartimide formation, especially Asp-Gly or Asn-Gly at positions 28 and 29.
- WO 2015/155141 A1 provides exendin-4 analogues with only 4 or 5 amino acid modifications compared to native exendin-4 which potently activate not only the GLP-1 receptor but also the glucagon receptor and optionally the GIP receptor.
- WO 2014/096145 A1 similarly relates to exendin-4 analogues which potently activate the GLP and the GIP receptor and optionally the glucagon receptor.
- the general formula differs from the present formula I.
- WO 2013/192129 A1 provides peptides that are GIP agonist peptides contemplated for use in treating subjects in need thereof, e.g. with diabetes and obesity.
- WO 2015/067716 A1 concerns glucagon/GLP-1/GIP triple agonists, which comprise one or more substitutions as compared to wild-type glucagon and which may have the property of an altered, preferably increased GIP and GLP-1 receptor activity.
- WO 2016/198624 A1 relates to exendin-4 derivatives, which in addition to the agonistic activity at the GLP-1 receptor of native exendin-4 show agonistic activity at the glucagon receptor and the GIP receptor and have, among others, the following modifications: at position 2 an alpha-aminoisobutyric acid, at position 3 a histidine, at position 17 a glutamine, at position 18 a leucine and at position 27 an isoleucine.
- residues Tyr10 and Tyr13 which are known to contribute to the fibrillation of glucagon ( JS Pedersen et al., Biochemistry, 2006, 45, 14503-14512 ) are replaced by Leu.
- This replacement especially in combination with isoleucine in position 23 and glutamate in position 24, leads to exendin-4 derivatives with potentially improved biophysical properties as solubility or aggregation behaviour in solution.
- Native exendin-4 is a pure GLP-1 receptor agonist without activity on the glucagon receptor and low activity on the GIP receptor.
- the compounds of the invention are based on the structure of native exendin-4 but differing at fourteen or more positions as compared to SEQ ID NO: 4 wherein the differences contribute to the enhancement of the agonistic activity at the glucagon receptor and the GIP receptor.
- substitutions - methionine at position 14 is replaced by an amino acid carrying an -NH 2 group in the side-chain, which is further substituted by a lipophilic residue (e.g. a fatty acid combined with a linker).
- the compounds of the invention are GLP-1, glucagon and GIP receptor agonists as determined by the observation that they are capable of stimulating intracellular cAMP formation in the assay system described in Methods.
- the compounds of the invention exhibit at least a relative activity of 0.1% (i.e. EC 50 ⁇ 700 pM), more preferably of 1% (i.e. EC 50 ⁇ 70 pM), more preferably of 5% (i.e. EC 50 ⁇ 14 pM) and even more preferably of 10% (i.e. EC 50 ⁇ 7 pM) compared to that of GLP-1(7-36)amide at the GLP-1 receptor.
- the compounds of the invention exhibit at least a relative activity of 0.1% (i.e. EC 50 ⁇ 500 pM), more preferably of 0.25% (i.e.
- the compounds of the invention exhibit at least a relative activity of 0.1% (i.e. EC 50 ⁇ 400 pM), more preferably of 0.4% (i.e. EC 50 ⁇ 100 pM), more preferably of 1% ( ⁇ 40 pM) and even more preferably of 2% (i.e. EC 50 ⁇ 20 pM) compared to that of natural GIP at the GIP receptor.
- the term "activity" as used herein preferably refers to the capability of a compound to activate the human GLP-1 receptor, the human glucagon receptor and the human GIP receptor. More preferably the term “activity” as used herein refers to the capability of a compound to stimulate intracellular cAMP formation.
- the term "relative activity” as used herein is understood to refer to the capability of a compound to activate a receptor in a certain ratio as compared to another receptor agonist or as compared to another receptor. The activation of the receptors by the agonists (e.g. by measuring the cAMP level) is determined as described herein, e.g. as described in the examples.
- the compounds of the invention preferably have an EC 50 for hGLP-1 receptor of 450 pM or less, preferably of 200 pM or less, more preferably of 100 pM or less, more preferably of 50 pM or less, more preferably of 25 pM or less, more preferably of 10 pM or less, more preferably of 8 pM or less, and more preferably of 5 pM or less and an EC 50 for hGlucagon receptor of 450 pM or less, preferably of 200 pM or less, more preferably of 100 pM or less, more preferably of 50 pM or less, and an EC 50 for hGIP receptor of 450 pM or less, preferably of 200 pM or less, more preferably of 100 pM or less, more preferably of 50 pM or less, more preferably of 25 pM or less.
- the EC 50 for the hGLP-1 receptor, the hGlucagon receptor and the hGIP receptor may be determined as described
- the compounds of formula I do not only show high activity on the glucagon receptor but as well on the GIP receptor.
- the additional high activity on the GIP receptor is intended for enhanced efficacy on blood glucose control compared to pure GLP-1 receptor agonism and to reduce the probability of GLP-1 related side effects like gastrointestinal distress as the contribution of the GLP-1 part can be reduced.
- the additional GIP receptor activity is also intended to counterbalance a potential glucose increase by glucagon receptor activation therefore allowing higher glucagon receptor activity as observed in compounds of formula I ( Finan et al. Nat Med. 2015, 21, 27-36 ).
- the compounds of the invention have a high solubility at acidic and/or physiological pH values in the presence of an antimicrobial preservative like phenol or m-cresol, e.g., at an acidity range from pH 4 to 5, especially pH 4.5 and/or a more physiological range from pH 6 to 8, especially at pH 7.4 at 25°C or 40°C, in another embodiment at least 1 mg/ml and in a particular embodiment at least 5 mg/ml.
- an antimicrobial preservative like phenol or m-cresol
- the compounds of the invention preferably have a high stability when stored in solution in the presence of an antimicrobial preservative like phenol or m-cresol.
- Preferred assay conditions for determining the stability is storage for 28 days at 25°C or 40°C in solution at an acidity range from pH 4 to 5, especially pH 4.5.
- the stability of peptide is determined by chromatographic analyses as described in the Methods.
- the purity loss is no more than 20%, more preferably no more than 15%, more preferably no more than 12% and even more preferably no more than 10%.
- the compounds of the invention show a hydrodynamic radius R h of 5 nm or less at concentrations of ⁇ 1 mg/ml in the presence of an antimicrobial preservative like phenol or m-cresol, e.g., at an acidity range from pH 4 to 5 at 25°C, especially pH 4.5 at 25°C as assayed by dynamic light scattering as described in Methods.
- an antimicrobial preservative like phenol or m-cresol
- the compounds of the invention do not show an increase in fluorecense intensity with Thioflavin T as fluorescence probe at concentrations of 3 mg/ml in the presence of an antimicrobial preservative like phenol or m-cresol, e.g., at an acidity range from pH 4 to 5, especially pH 4.5 at 37°C over 5 hours, more preferably over 10 hours, more preferably over 20 hours, more preferably over 30 hours, more preferably over 40 hours and even more preferably over 45 hours as assayed by the Tht assay as described in Methods.
- an antimicrobial preservative like phenol or m-cresol
- the compounds of this invention are more resistant to cleavage by neutral endopeptidase (NEP) and dipeptidyl peptidase-4 (DPP4), resulting in a longer half-life and duration of action in vivo, when compared with native GLP-1 and glucagon.
- NEP neutral endopeptidase
- DPP4 dipeptidyl peptidase-4
- the compounds of the present invention comprise a peptide moiety which is a linear sequence of 39 amino carboxylic acids, particularly ⁇ -amino carboxylic acids linked by peptide, i.e. carboxamide bonds.
- R 1 is NH 2 .
- stereoisomers particularly enantiomers of these groups, either S- or R-enantiomers.
- R in Table 2 is intended to mean the attachment site of -Z-C(O)-R 5 at the peptide back bone, for example the epsilon-amino group of Lys.
- a further embodiment relates to compounds of formula I, wherein
- a further embodiment relates to compounds of formula I, wherein
- a further embodiment relates to compounds of formula I, wherein
- a further embodiment relates to compounds of formula I, wherein
- a further embodiment relates to compounds of formula I, wherein
- a further embodiment relates to compounds of formula I, wherein
- a further embodiment relates to compounds of formula I, wherein
- a further embodiment relates to compounds of formula I, wherein
- a further embodiment relates to compounds of formula I, wherein
- a further embodiment relates to compounds of formula I, wherein
- a further embodiment relates to compounds of formula I, wherein
- a still further embodiment relates to compounds of formula I, wherein
- a specific example of compounds of formula I is the compound of SEQ ID NO: 6, well as salts or solvates thereof.
- a specific example of compounds of formula I is the compound of SEQ ID NO: 9, well as salts or solvates thereof.
- a specific example of peptidic compounds of formula I is the compound of SEQ ID NO: 11, well as salts or solvates thereof.
- the present invention relates to a composition
- a composition comprising a compound of the invention in admixture with a carrier.
- the composition is a pharmaceutically acceptable composition and the carrier is a pharmaceutically acceptable carrier.
- the compound of the invention may be in the form of a salt, e.g. a pharmaceutically acceptable salt or a solvate, e.g. a hydrate.
- the present invention relates to a composition for use in a method of medical treatment, particularly in human medicine.
- the compounds of formula I are suitable for use in human treatment without an additional therapeutically effective agent. In other embodiments, however, the compounds may be used together with at least one additional therapeutically active agent, as described in "combination therapy”.
- the compounds of formula I are particularly suitable for use in the treatment or prevention of diseases or disorders caused by, associated with and/or accompanied by disturbances in carbohydrate and/or lipid metabolism, e.g. for the treatment or prevention of hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity and metabolic syndrome. Further, the compounds of the invention may be suitable for use in the treatment or prevention of degenerative diseases, particularly neurodegenerative diseases.
- the compounds described find use, inter alia, in preventing weight gain or promoting weight loss.
- preventing is meant inhibiting or reducing when compared to the absence of treatment, and is not necessarily meant to imply complete cessation of a disorder.
- the compounds of the invention may cause a decrease in food intake and/or increase in energy expenditure, resulting in the observed effect on body weight.
- the compounds of the invention may have a beneficial effect on circulating cholesterol levels, being capable of improving lipid levels, particularly LDL, as well as HDL levels (e.g. increasing HDL/LDL ratio).
- the compounds of the invention may be used for direct or indirect therapy of any condition caused or characterised by excess body weight, such as the treatment and/or prevention of obesity, morbid obesity, obesity linked inflammation, obesity linked gallbladder disease, obesity induced sleep apnea. They may also be used for treatment and prevention of the metabolic syndrome, diabetes, hypertension, atherogenic dyslipidemia, atherosclerosis, arteriosclerosis, coronary heart disease, or stroke. Their effects in these conditions may be as a result of or associated with their effect on body weight, or may be independent thereof.
- Medical uses include delaying or preventing disease progression in type 2 diabetes, treating metabolic syndrome, treating obesity or preventing overweight, for decreasing food intake, increase energy expenditure, reducing body weight, delaying the progression from impaired glucose tolerance (IGT) to type 2 diabetes; delaying the progression from type 2 diabetes to insulin-requiring diabetes; and hepatic steatosis.
- ITT impaired glucose tolerance
- amino acid sequences of the present invention contain the conventional one letter and three letter codes for naturally occurring amino acids, as well as generally accepted three letter codes for other amino acids, such as Aib (a-aminoisobutyric acid).
- native exendin-4" refers to native exendin-4 having the sequence HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH 2 (SEQ ID NO: 4).
- the invention relates to peptidic compounds as defined in formula I.
- the peptidic compounds of the present invention comprise a linear backbone of amino carboxylic acids linked by peptide, i.e. carboxamide bonds.
- the amino carboxylic acids are ⁇ -amino carboxylic acids and more preferably L- ⁇ -amino carboxylic acids, unless indicated otherwise.
- the peptidic compounds preferably comprise a backbone sequence of 39 amino carboxylic acids.
- Amino acids within the peptide moiety can be considered to be numbered consecutively from 1 to 39 in the conventional N-terminal to C-terminal direction.
- Reference to a "position" within peptidic moiety I should be constructed accordingly, as should reference to positions within native exendin-4 and other molecules, e.g., in exendin-4, His is at position 1, Gly at position 2, ..., Met at position 14, ... and Ser at position 39.
- An amino acid residue with an -NH 2 side chain group e.g. Lys, Orn, Dab or Dap, is functionalized in that at least one H atom of the -NH 2 side chain group is replaced by -Z-C(O)-R 5 , wherein R 5 comprises a lipophilic moiety, e.g. an acyclic linear or branched (C 8 -C 30 ) saturated or unsaturated hydrocarbon group, which is unsubstituted or substituted e.g. by halogen (F, Cl, Br, J), -OH and/or CO 2 H and Z comprises a linker in all stereoisomeric forms, e.g. a linker comprising one or more, e.g.
- R 5 comprises a lipophilic moiety, e.g. an acyclic linear or branched (C 8 -C 30 ) saturated or unsaturated hydrocarbon group, which is unsubstituted or substituted e.g. by halogen (F,
- Preferred groups R 5 comprise a lipophilic moiety, e.g. an acyclic linear or branched (C 12 -C 20 ) saturated or unsaturated hydrocarbon group, e.g. pentadecanyl, hexadecanyl or heptadecanyl, which is unsubstituted or substituted by CO 2 H, more preferably pentadecanyl, or heptadecanyl.
- amino acid linker groups are selected from gGlu, gGlu-gGlu, gGlu-gGlu-AEEAc, gGlu-AEEAc-gAAA, AEEAc-AEEAc-gGlu and AEEAc-AEEAc-AEEAc.
- the amino acid linker group is gGlu.
- the amino acid linker group is gGlu-gGlu.
- the amino acid linker group is gGlu-gGlu-AEEAc.
- amino acid linker group is gGlu-AEEAc-gAAA.
- amino acid linker group is AEEAc-AEEAc-gGlu.
- amino acid linker group is AEEAc-AEEAc-AEEAc.
- the present invention relates to a composition
- a composition comprising a compound of the invention as described herein, or a salt or solvate thereof, in admixture with a carrier.
- the invention also relates to the use of a compound of the present invention for use as a medicament, particularly for the treatment of a condition as described in the specification.
- the invention also relates to a composition wherein the composition is a pharmaceutically acceptable composition, and the carrier is a pharmaceutically acceptable carrier.
- peptides The skilled person is aware of a variety of different methods to prepare peptides. These methods include but are not limited to synthetic approaches and recombinant gene expression. Thus, one way of preparing these peptides is the synthesis in solution or on a solid support and subsequent isolation and purification. A different way of preparing the peptides is gene expression in a host cell in which a DNA sequence encoding the peptide has been introduced. Alternatively, the gene expression can be achieved without utilizing a cell system. The methods described above may also be combined in any way.
- Solid phase peptide synthesis is a well-established methodology (see for example: Stewart and Young, Solid Phase Peptide Synthesis, Pierce Chemical Co., Rockford, III., 1984 ; E. Atherton and R. C. Sheppard, Solid Phase Peptide Synthesis. A Practical Approach, Oxford-IRL Press, New York, 1989 ).
- Solid phase synthesis is initiated by attaching an N-terminally protected amino acid with its carboxy terminus to an inert solid support carrying a cleavable linker.
- This solid support can be any polymer that allows coupling of the initial amino acid, e.g.
- trityl resin a chlorotrityl resin, a Wang resin or a Rink resin in which the linkage of the carboxy group (or carboxamide for Rink resin) to the resin is sensitive to acid (when Fmoc strategy is used).
- the polymer support must be stable under the conditions used to deprotect the ⁇ -amino group during the peptide synthesis.
- the ⁇ -amino protecting group of this amino acid is removed.
- the remaining protected amino acids are then coupled one after the other or with a preformed dipeptide, tripeptide or tetrapeptide in the order represented by the peptide sequence using appropriate amide coupling reagents, for example BOP, HBTU, HATU or DIC (N,N'-diisopropylcarbodiimide) / HOBt (1-hydroxybenzotriazole), wherein BOP, HBTU and HATU are used with tertiary amine bases.
- the liberated N-terminus can be functionalized with groups other than amino acids, for example carboxylic acids, etc.
- a lysine may be protected with an ivDde ([1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl) protecting group ( S.R. Chhabra et al., Tetrahedron Lett. 39, (1998), 1603 ) which is labile to a very nucleophilic base, for example 4% hydrazine in DMF (dimethyl formamide).
- ivDde [1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl
- the ivDde group can be selectively removed using 4% hydrazine in DMF and the corresponding free amino group can then be further modified, e.g. by acylation.
- the lysine can alternatively be coupled to a protected amino acid and the amino group of this amino acid can then be deprotected resulting in another free amino group which can be acylated or attached to further amino acids.
- the side chain (as described in table 2) can be introduced together with the lysine during peptide synthesis using a prefunctionalized building block, e.g.
- peptide is cleaved from the resin. This can be achieved by using King's cocktail ( D. S. King, C. G. Fields, G. B. Fields, Int. J. Peptide Protein Res. 36, 1990, 255-266 ).
- the raw material can then be purified by chromatography, e.g. preparative RP-HPLC, if necessary.
- potency or “in vitro potency” is a measure for the ability of a compound to activate the receptors for GLP-1, glucagon or GIP in a cell-based assay. Numerically, it is expressed as the "EC50 value", which is the effective concentration of a compound that induces a half maximal increase of response (e.g. formation of intracellular cAMP) in a dose-response experiment.
- Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing type 2 diabetes, as well as atherosclerotic vascular disease, e.g. heart disease and stroke.
- Defining medical parameters for the metabolic syndrome include diabetes mellitus, impaired glucose tolerance, raised fasting glucose, insulin resistance, urinary albumin secretion, central obesity, hypertension, elevated triglycerides, elevated LDL cholesterol and reduced HDL cholesterol.
- Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health and life expectancy and due to its increasing prevalence in adults and children it has become one of the leading preventable causes of death in modern world. It increases the likelihood of various other diseases, including heart disease, type 2 diabetes, obstructive sleep apnoe, certain types of cancer, as well as osteoarthritis, and it is most commonly caused by a combination of excess food intake, reduced energy expenditure, as well as genetic susceptibility.
- Diabetes mellitus often simply called diabetes, is a group of metabolic diseases in which a person has high blood sugar levels, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced.
- the most common types of diabetes are: (1) type 1 diabetes, where the body fails to produce insulin; (2) type 2 diabetes (T2DM), where the body fails to use insulin properly, combined with an increase in insulin deficiency over time, and (3) gestational diabetes, where women develop diabetes due to their pregnancy. All forms of diabetes increase the risk of long-term complications, which typically develop after many years.
- macrovascular disease arising from atherosclerosis of larger blood vessels
- microvascular disease arising from damage of small blood vessels.
- macrovascular disease conditions are ischemic heart disease, myocardial infarction, stroke and peripheral vascular disease.
- microvascular diseases are diabetic retinopathy, diabetic nephropathy, as well as diabetic neuropathy.
- the receptors for GLP-1 and GIP as well as glucagon are members of the family of 7-transmembrane-spanning, heterotrimeric G-protein coupled receptors. They are structurally related to each other and share not only a significant level of sequence identity, but have also similar mechanisms of ligand recognition and intracellular signaling pathways.
- GLP-1, GIP and glucagon share regions of high sequence identity/similarity.
- GLP-1 and glucagon are produced from a common precursor, preproglucagon, which is differentially processed in a tissue-specific manner to yield e.g. GLP-1 in intestinal endocrine cells and glucagon in alpha cells of pancreatic islets.
- GIP is derived from a larger proGIP prohormone precursor and is synthesized and released from K-cells located in the small intestine.
- the peptidic incretin hormones GLP-1 and GIP are secreted by intestinal endocrine cells in response to food and account for up to 70% of meal-stimulated insulin secretion.
- targeting of the GLP-1 receptor with suitable agonists offers an attractive approach for treatment of metabolic disorders, including diabetes.
- the receptor for GLP-1 is distributed widely, being found mainly in pancreatic islets, brain, heart, kidney and the gastrointestinal tract. In the pancreas, GLP-1 acts in a strictly glucose-dependent manner by increasing secretion of insulin from beta cells.
- the receptor for GIP is broadly expressed in peripheral tissues including pancreatic islets, adipose tissue, stomach, small intestine, heart, bone, lung, kidney, testis, adrenal cortex, pituitary, endothelial cells, trachea, spleen, thymus, thyroid and brain. Consistent with its biological function as incretin hormone, the pancreatic ⁇ -cell express the highest levels of the receptor for GIP in humans.
- GIP-receptor mediated signaling could be impaired in patients with T2DM but the impairment of GIP-action is shown to be reversible and could be restored with improvement of the diabetic status.
- the stimulation of insulin secretion by both incretin hormones, GIP and GLP-1 is strictly glucose-dependent ensuring a fail-safe mechanism associated with a low risk for hypoglycemia.
- GLP-1 and GIP have been shown to promote glucose sensitivity, neogenesis, proliferation, transcription of proinsulin and hypertrophy, as well as anti-apoptosis.
- a peptide with both agonistic activity for the GLP-1 and the GIP receptor could be anticipated to have additive or synergistic anti-diabetic benefit.
- Other relevant effects of GLP-1 beyond the pancreas include delayed gastric emptying, increased satiety, decreased food intake, reduction of body weight, as well as neuroprotective and cardioprotective effects. In patients with type 2 diabetes, such extrapancreatic effects could be particularly important considering the high rates of comorbidities like obesity and cardiovascular disease.
- Further GIP actions in peripheral tissues beyond the pancreas comprise increased bone formation and decreased bone resorption as well as neuroprotective effects which might be beneficial for the treatment of osteoporosis and cognitive defects like Alzheimer's disease.
- Glucagon is a 29 amino acid peptide hormone that is produced by pancreatic alpha cells and released into the bloodstream when circulating glucose is low.
- An important physiological role of glucagon is to stimulate glucose output in the liver, which is a process providing the major counterregulatory mechanism for insulin in maintaining glucose homeostasis in vivo.
- Glucagon receptors are however also expressed in extra-hepatic tissues such as kidney, heart, adipocytes, lymphoblasts, brain, retina, adrenal gland and gastrointestinal tract, suggesting a broader physiological role beyond glucose homeostasis. Accordingly, recent studies have reported that glucagon has therapeutically positive effects on energy management, including stimulation of energy expenditure and thermogenesis, accompanied by reduction of food intake and body weight loss. Altogether, stimulation of glucagon receptors might be useful in the treatment of obesity and the metabolic syndrome.
- Oxyntomodulin is a peptide hormone consisting of glucagon with an eight amino acids encompassing C-terminal extension. Like GLP-1 and glucagon, it is pre-formed in preproglucagon and cleaved and secreted in a tissue-specific manner by endocrinal cells of the small bowel. Oxyntomodulin is known to stimulate both, the receptors for GLP-1 and glucagon and is therefore the prototype of a dual agonist (see Pocai, Molecular Metabolism 2013; 3:241-51 ).
- GLP-1 and GIP are known for their anti-diabetic effects
- GLP-1 and glucagon are both known for their food intake-suppressing effects
- glucagon is also a mediator of additional energy expenditure, it is conceivable that a combination of the activities of the three hormones in one molecule can yield a powerful medication for treatment of the metabolic syndrome and in particular its components diabetes and obesity.
- the compounds of the invention may be used for treatment of glucose intolerance, insulin resistance, pre-diabetes, increased fasting glucose (hyperglycemia), type 2 diabetes, hypertension, dyslipidemia, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke or any combination of these individual disease components.
- they may be used for control of appetite, feeding and calory intake, increase of energy expenditure, prevention of weight gain, promotion of weight loss, reduction of excess body weight and altogether treatment of obesity, including morbid obesity.
- the compounds of the invention are agonists for the receptors for GLP-1, GIP and for glucagon (e.g. "trigonal agonists") and may provide therapeutic benefit to address a clinical need for targeting the metabolic syndrome by allowing simultaneous treatment of diabetes and obesity.
- the effects of the compounds of the invention may be mediated in whole or in part via an effect on body weight, or independent thereof.
- diseases to be treated may be neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease, or other degenerative diseases as described above.
- the compounds are useful in the treatment or prevention of hyperglycemia, type 2 diabetes and/or obesity.
- the compounds of the invention may have the ability to reduce the intestinal passage, increase the gastric content and/or to reduce the food intake of a patient. These activities of the compounds of the invention can be assessed in animal models known to the skilled person and also described herein in the Methods.
- the compounds of the invention have the ability to reduce blood glucose level, and/or to reduce HbA1c levels of a patient. These activities of the compounds of the invention can be assessed in animal models known to the skilled person and also described herein in the Methods and in examples.
- the compounds of the invention may have the ability to reduce body weight of a patient. These activities of the compounds of the invention can be assessed in animal models known to the skilled person and also described herein in the Methods and in examples.
- the compounds of the invention may be useful in the treatment or prevention of hepatosteatosis, preferably non-alcoholic liver-disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
- NAFLD non-alcoholic liver-disease
- NASH non-alcoholic steatohepatitis
- composition indicates a mixture containing ingredients that are compatible when mixed and which may be administered.
- a pharmaceutical composition may include one or more medicinal drugs. Additionally, the pharmaceutical composition may include carriers, buffers, acidifying agents, alkalizing agents, solvents, adjuvants, tonicity adjusters, emollients, expanders, preservatives, physical and chemical stabilizers e.g. surfactants, antioxidants and other components, whether these are considered active or inactive ingredients.
- Guidance for the skilled in preparing pharmaceutical compositions may be found, for example, in Remington: The Science and Practice of Pharmacy, (20th ed.) ed. A. R. Gennaro, 2000, Lippencott Williams & Wilkins and in R.C.Rowe et al (Ed), Handbook of Pharmaceutical Excipients, PhP, May 2013 update.
- exendin-4 peptide derivatives of the present invention are administered in conjunction with an acceptable pharmaceutical carrier, diluent, or excipient as part of a pharmaceutical composition.
- a “pharmaceutically acceptable carrier” is a carrier which is physiologically acceptable (e.g. physiologically acceptable pH) while retaining the therapeutic properties of the substance with which it is administered.
- Standard acceptable pharmaceutical carriers and their formulations are known to one skilled in the art and described, for example, in Remington: The Science and Practice of Pharmacy, (20th ed.) ed. A. R. Gennaro , 2000, Lippencott Williams & Wilkins and in R.C.Rowe et al (Ed ), Handbook of Pharmaceutical excipients, PhP, May 2013 update.
- One exemplary pharmaceutically acceptable carrier is physiological saline solution.
- carriers are selected from the group of buffers (e.g. citrate/citric acid, acetate/acetic acid), acidifying agents (e.g. hydrochloric acid), alkalizing agents (e.g. sodium hydroxide), preservatives (e.g. phenol, m-cresol), co-solvents (e.g. polyethylene glycol 400), tonicity adjusters (e.g. mannitol, glycerol), stabilizers (e.g. surfactant, antioxidants, amino acids).
- buffers e.g. citrate/citric acid, acetate/acetic acid
- acidifying agents e.g. hydrochloric acid
- alkalizing agents e.g. sodium hydroxide
- preservatives e.g. phenol, m-cresol
- co-solvents e.g. polyethylene glycol 400
- tonicity adjusters e.g. mannitol, glycerol
- stabilizers e.
- Concentrations used are in a range that is physiologically acceptable.
- Acceptable pharmaceutical carriers or diluents include those used in formulations suitable for oral, rectal, nasal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and transdermal) administration.
- the compounds of the present invention will typically be administered parenterally.
- pharmaceutically acceptable salt means salts of the compounds of the invention which are safe and effective for use in mammals.
- solvate means complexes of the compounds of the invention or salts thereof with solvent molecules, e.g. organic solvent molecules and/or water.
- the exendin-4 derivative in monomeric or oligomeric form.
- terapéuticaally effective amount of a compound refers to a nontoxic but sufficient amount of the compound to provide the desired effect.
- the amount of a compound of the formula I necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient.
- An appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
- the "therapeutically effective amount” of a compound of the formula I is about 0.01 to 50 mg/dose, preferably 0.02 to 1 mg/dose.
- compositions of the invention are those suitable for parenteral (for example subcutaneous, intramuscular, intradermal or intravenous), rectal, topical and peroral (for example sublingual) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula I used in each case.
- application is parenteral, e.g. subcutaneous.
- the corresponding formulations could be favorable for the corresponding formulations to include at least one antimicrobial preservative in order to inhibit the growth of microbes and bacteria between administrations.
- Preferred preservatives are benzylic alcohol or phenolic compounds like phenol or m-cresol. It has been described that these ingredients can induce aggregation for peptides and proteins leading to lower solubility and stability in the formulation (see R. L. Bis et al., Int. J. Pharm. 472, 356-361, 2014 ; T. J. Kamerzell, Adv. Drug Deliv. Rev., 63, 1118-1159, 2011 ).
- Suitable pharmaceutical compositions may be in the form of separate units, for example capsules, tablets and powders in vials or ampoules, each of which contains a defined amount of the compound; as powders or granules; as solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. It may be provided in single or multiple dose injectable form, for example in the form of a pen.
- the compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact.
- the pharmaceutical composition may be provided together with a device for application, for example together with a syringe, an injection pen or an autoinjector.
- a device for application for example together with a syringe, an injection pen or an autoinjector.
- Such devices may be provided separate from a pharmaceutical composition or prefilled with the pharmaceutical composition.
- the compound(s) of the present invention can be prepared for use in suitable pharmaceutical compositions.
- suitable pharmaceutical compositions may be in the form of one or more administration units.
- compositions may be prepared by any suitable pharmaceutical method which includes a step in which the compound(s) of the present invention and the carrier (which may consist of one or more additional ingredients) are brought into contact.
- the administration units may be for example capsules, tablets, dragées, granules sachets, drops, solutions, suspensions, lyophylisates and powders, each of which contains a defined amount of the compound(s) of the present invention.
- Each of the above-mentioned administration units of the compound(s) of the invention or pharmaceutical composition of the invention may be provided in a package for easy transport and storage.
- the administration units are packaged in standard single or multi-dosage packaging, their form, material and shape depending on the type of units prepared.
- tablets and other forms of solid administration units can be packaged in single units, and the single packaged units can be packaged in multi-pack containers.
- Liquid formulations can be packaged in single units, such as e.g. vials, cartridges, syringes/prefilled syringes, infusion bags, collapsible plastic bags, infusion bottles, blow-filled seal bottles or infusion tubings or in single or multiple dose injectable form, for example in the form of a pen device, pump or syringe and the single packaged units can be packaged in multi-pack containers.
- a single package may comprise only one or a plurality of administration units.
- the package may for example be made of paper, cardboard, paperboard, plastic, metal, combinations or laminates of one or more of paper, plastics and metal, or glass.
- Exemplary embodiments are blister packages containing e.g. tablets or capsules, which in turn may be provided inside a cardboard box, aluminum barrier laminate sachets containing e.g. a powder, glass or plastic bottles containing e.g. tablets or a solution, or vials, cartridges, syringes, infusion bags, infusion bottles, infusion tubings or ampoules containing a solution or suspension.
- administration units may be provided together with a device for application, for example together with a syringe, an injection pen or an autoinjector.
- a device for application for example together with a syringe, an injection pen or an autoinjector.
- Such devices may be provided separate from a pharmaceutical composition or prefilled with the pharmaceutical composition.
- a “pen-type injection device”, often briefly referred to as “injection pen”, is typically an injection device having an elongated shape that resembles to a fountain pen for writing. Although such pens usually have a tubular cross-section, they could easily have a different cross-section such as triangular, rectangular or square or any variation around these geometries.
- pen-type injection devices comprise three primary elements: a cartridge section that includes a cartridge often contained within a housing or holder; a needle assembly connected to one end of the cartridge section; and a dosing section connected to the other end of the cartridge section.
- the cartridge typically includes a reservoir that is filled with a medication, a movable rubber type bung or stopper located at one end of the cartridge reservoir, and a top having a pierceable rubber seal located at the other, often necked-down, end.
- a crimped annular metal band is typically used to hold the rubber seal in place. While the cartridge housing may be typically made of plastic, cartridge reservoirs have historically been made of glass.
- the compounds of the present invention can be widely combined with other pharmacologically active compounds, such as all drugs mentioned in the Rote Liste 2016, e.g. with all weight-reducing agents or appetite suppressants mentioned in the Rote Liste 2016, chapter 1, all lipid-lowering agents mentioned in the Rote Liste 2016, chapter 58, all antihypertensives and nephroprotectives, mentioned in the Rote Liste 2016, or all diuretics mentioned in the Rote Liste 2015, chapter 36.
- the active ingredient combinations can be used especially for a synergistic improvement in action. They can be applied either by separate administration of the active ingredients to the patient or in the form of combination products in which a plurality of active ingredients are present in one pharmaceutical preparation. When the active ingredients are administered by separate administration of the active ingredients, this can be done simultaneously or successively.
- active substances which are suitable for such combinations include in particular those which for example potentiate the therapeutic effect of one or more active substances with respect to one of the indications mentioned and/or which allow the dosage of one or more active substances to be reduced.
- Therapeutic agents which are suitable for combinations include, for example, antidiabetic agents such as: Insulin and Insulin derivatives, for example: Glargine / Lantus ® , 270 - 330U/mL of insulin glargine ( EP 2387989 A ), 300U/mL of insulin glargine ( EP 2387989 A ), Glulisin /Apidra ® , Detemir / Levemir ® , Lispro / Humalog ® / Liprolog ® , Degludec / DegludecPlus, Aspart, basal insulin and analogues (e.g.LY-2605541, LY2963016, NN1436), PEGylated insulin Lispro, Humulin ® , Linjeta, SuliXen ® , NN1045, Insulin plus Symlin, PE0139, fast-acting and short-acting insulins (e.g.
- Linjeta PH20, NN1218, HinsBet
- API-002 hydrogel
- oral, inhalable, transdermal and sublingual insulins e.g. Exubera ® , Nasulin ® , Afrezza, Tregopil, TPM 02, Capsulin, Oral-lyn ® , Cobalamin ® oral insulin, ORMD-0801, NN1953, NN1954, NN1956, VIAtab, Oshadi oral insulin.
- insulin derivatives which are bonded to albumin or another protein by a bifunctional linker.
- GLP-1, GLP-1 analogues and GLP-1 receptor agonists for example: Lixisenatide / AVE0010 / ZP10 / Lyxumia, Exenatide / Exendin-4 / Byetta / Bydureon / ITCA 650 / AC-2993, Liraglutide / Victoza, Semaglutide, Taspoglutide, Syncria / Albiglutide, Dulaglutide, rExendin-4, CJC-1134-PC, PB-1023, TTP-054, Efpeglenatide / HM-11260C, CM-3, GLP-1 Eligen, ORMD-0901, NN-9924, NN-9926, NN-9927, Nodexen, Viador-GLP-1, CVX-096, ZYOG-1, ZYD-1, GSK-2374697, DA-3091, MAR-701, MAR709, ZP-2929, ZP-3022, ZP-DI-
- DPP-4 inhibitors for example: Alogliptin / Nesina, Trajenta / Linagliptin / BI-1356 / Ondero / Trajenta / Tradjenta / Trayenta / Tradzenta, Saxagliptin / Onglyza, Sitagliptin / Januvia / Xelevia / Tesave / Janumet / Velmetia, Galvus / Vildagliptin, Anagliptin, Gemigliptin, Teneligliptin, Melogliptin, Trelagliptin, DA-1229, Omarigliptin / MK-3102, KM-223, Evogliptin, ARI-2243, PBL-1427, Pinoxacin.
- SGLT2 inhibitors for example: Invokana / Canaglifozin, Forxiga / Dapagliflozin, Remoglifozin, Sergliflozin, Empagliflozin, Ipragliflozin, Tofogliflozin, Luseogliflozin, Sotagliflozin (LX-4211), Ertuglifozin / PF-04971729, RO-4998452, Bexagliflozin (EGT-0001442), KGA-3235 / DSP-3235, LIK066, SBM-TFC-039, Henagliflozin (SHR3824), Janagliflozin, Tianagliflozin, AST1935, JRP493, HEC-44616 Biguanides (e.g.
- Metformin, Buformin, Phenformin), Thiazolidinediones e.g. Pioglitazone, Rivoglitazone, Rosiglitazone, Troglitazone
- dual PPAR agonists e.g. Aleglitazar, Muraglitazar, Tesaglitazar
- Sulfonylureas e.g. Tolbutamide, Glibenclamide, Glimepiride/Amaryl, Glipizide
- Meglitinides e.g. Nateglinide, Repaglinide, Mitiglinide
- Alpha-glucosidase inhibitors e.g. Acarbose, Miglitol, Voglibose
- Amylin and Amylin analogues e.g. Pramlintide, Symlin.
- GPR119 agonists e.g. GSK-263A, PSN-821, MBX-2982, APD-597, ZYG-19, DS-8500
- GPR40 agonists e.g. Fasiglifam / TAK-875, TUG-424, P-1736, JTT-851, GW9508.
- Suitable combination partners are: Cycloset, inhibitors of 11-beta-HSD (e.g. LY2523199, BMS770767, RG-4929, BMS816336, AZD-8329, HSD-016, BI-135585), activators of glucokinase (e.g. TTP-399, AMG-151, TAK-329, GKM-001), inhibitors of DGAT (e.g. LCQ-908), inhibitors of protein tyrosinephosphatase 1 (e.g.
- Trodusquemine inhibitors of glucose-6-phosphatase, inhibitors of fructose-1,6-bisphosphatase, inhibitors of glycogen phosphorylase, inhibitors of phosphoenol pyruvate carboxykinase, inhibitors of glycogen synthase kinase, inhibitors of pyruvate dehydrokinase, alpha2-antagonists, CCR-2 antagonists, SGLT-1 inhibitors (e.g. LX-2761).
- One or more lipid lowering agents are also suitable as combination partners, such as for example: HMG-CoA-reductase inhibitors (e.g. Simvastatin, Atorvastatin), fibrates (e.g. Bezafibrate, Fenofibrate), nicotinic acid and the derivatives thereof (e.g. Niacin), PPAR-(alpha, gamma or alpha/gamma) agonists or modulators (e.g. Aleglitazar), PPAR-delta agonists, ACAT inhibitors (e.g. Avasimibe), cholesterol absorption inhibitors (e.g. Ezetimibe), Bile acid-binding substances (e.g. Cholestyramine), ileal bile acid transport inhibitors, MTP inhibitors, or modulators of PCSK9.
- HMG-CoA-reductase inhibitors e.g. Simvastatin, Atorvastatin
- fibrates e.g. Bezafib
- HDL-raising compounds such as: CETP inhibitors (e.g. Torcetrapib, Anacetrapid, Dalcetrapid, Evacetrapid, JTT-302, DRL-17822, TA-8995) or ABC1 regulators.
- CETP inhibitors e.g. Torcetrapib, Anacetrapid, Dalcetrapid, Evacetrapid, JTT-302, DRL-17822, TA-8995
- ABC1 regulators e.g., ABC1 regulators.
- Suitable combination partners are one or more active substances for the treatment of obesity, such as for example: Sibutramine, Tesofensine, Orlistat, antagonists of the cannabinoid-1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists (e.g. Velneperit), beta-3-agonists, leptin or leptin mimetics, agonists of the 5HT2c receptor (e.g. Lorcaserin), or the combinations of bupropione/naltrexone, bupropione/zonisamide, bupropione/phentermine or pramlintide/metreleptin.
- active substances for the treatment of obesity such as for example: Sibutramine, Tesofensine, Orlistat, antagonists of the cannabinoid-1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists (e.g. Velneperit), beta-3-agonists,
- angiotensin II receptor antagonists e.g. telmisartan, candesartan, valsartan, losartan, eprosartan, irbesartan, olmesartan, tasosartan, azilsartan
- ACE inhibitors e.g. telmisartan, candesartan, valsartan, losartan, eprosartan, irbesartan, olmesartan, tasosartan, azilsartan
- ACE inhibitors e.g. telmisartan, candesartan, valsartan, losartan, eprosartan, irbesartan, olmesartan, tasosartan, azilsartan
- ACE inhibitors e.g. telmisartan, candesartan, valsartan, losartan, eprosartan, irbe
- this invention relates to the use of a compound according to the invention or a physiologically acceptable salt thereof combined with at least one of the active substances described above as a combination partner, for preparing a medicament which is suitable for the treatment or prevention of diseases or conditions which can be affected by binding to the receptors for GLP-1 and glucagon and by modulating their activity.
- This is preferably a disease in the context of the metabolic syndrome, particularly one of the diseases or conditions listed above, most particularly diabetes or obesity or complications thereof.
- the use of the compound according to the invention, or a physiologically acceptable salt thereof, in combination with another active substance may take place simultaneously or at staggered times, but particularly within a short space of time. If they are administered simultaneously, the two active substances are given to the patient together; if they are used at staggered times, the two active substances are given to the patient within a period of less than or equal to 12 hours, but particularly less than or equal to 6 hours.
- this invention relates to a medicament which comprises a compound according to the invention or a physiologically acceptable salt of such a compound and at least one of the active substances described above as combination partners, optionally together with one or more inert carriers and/or diluents.
- the compound according to the invention, or physiologically acceptable salt or solvate thereof, and the additional active substance to be combined therewith may both be present together in one formulation, for example a tablet or capsule, or separately in two identical or different formulations, for example as so-called kit-of-parts.
- Rink-Amide resins (4-(2',4'-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucylaminomethyl resin, Merck Biosciences; 4-[(2,4-Dimethoxyphenyl)(Fmoc-amino)methyl]phenoxy acetamido methyl resin, Agilent Technologies) were used for the synthesis of peptide amides with loadings in the range of 0.2-0.7 mmol/g.
- Fmoc protected natural amino acids were purchased from Protein Technologies Inc., Senn Chemicals, Merck Biosciences, Novabiochem, Iris Biotech, Bachem, Chem-Impex International or MATRIX Innovation. The following standard amino acids were used throughout the syntheses: Fmoc-L-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-L-Asn(Trt)-OH, Fmoc-L-Asp(OtBu)-OH, Fmoc-L-Cys(Trt)-OH, Fmoc-L-Gln(Trt)-OH, Fmoc-L-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-L-His(Trt)-OH, Fmoc-L-Ile-OH, Fmoc-L-Leu-OH, Fmoc-L-Lys(Boc)-OH, Fmoc-
- building blocks (2S)-6-[[(4S)-5-tert-butoxy-4-[[(4S)-5-tert-butoxy-4-(hexadecanoylamino)-5-oxo-pentanoyl]amino]-5-oxo-pentanoyl]amino]-2-(9H-fluoren-9-ylmethoxycarbonylamino)hexanoic acid and Boc-L-His(Trt)-Aib-OH can be applied. Both building blocks are synthesized separately.
- the solid phase peptide syntheses were performed for example on a Prelude Peptide Synthesizer (Protein Technologies Inc) or similar automated synthesizer using standard Fmoc chemistry and HBTU/DIPEA activation. DMF was used as the solvent. Deprotection : 20% piperidine/DMF for 2 ⁇ 2.5 min. Washes: 7 ⁇ DMF. Coupling 2:5:10 200 mM AA/ 500 mM HBTU / 2M DIPEA in DMF 2 ⁇ for 20 min.
- Fmoc-L-Lys(ivDde)-OH or Fmoc-L-Lys(Mmt)-OH was used in the corresponding position.
- the ivDde group was removed according to a modified literature procedure ( S.R. Chhabra et al., Tetrahedron Lett., 1998, 39, 1603 ), using 4% hydrazine hydrate in DMF.
- the Mmt group was removed by repeated treatment with AcOH/TFE/DCM (1/2/7) for 15 minutes at RT, the resin then repeatedly washed with DCM, 5% DIPEA in DCM and 5% DIPEA in DCM/DMF.
- acylations were carried out by treating the resin with the N-hydroxy succinimide esters of the desired acid or using coupling reagents like HBTU/DIPEA or HOBt/DIC.
- peptides were synthesized by a manual synthesis procedure: 0.3 g Desiccated Rink amide MBHA Resin (0.66 mmol/g) was placed in a polyethylene vessel equipped with a polypropylene filter. Resin was swollen in DCM (15 ml) for 1 h and DMF (15 ml) for 1h. The Fmoc group on the resin was de-protected by treating it twice with 20% (v/v) piperidine/DMF solution for 5 and 15 min. The resin was washed with DMF/DCM/DMF (6:6:6 time each). A Kaiser test (quantitative method) was used for the conformation of removal of Fmoc from solid support.
- the unreacted amino group, if any, in the resin was capped used acetic anhydride/pyridine/DCM (1:8:8) for 20 minutes to avoid any deletion of the sequence.
- resin was washed with DCM/DMF/DCM/DMF (6/6/6/6 time each).
- the Fmoc group on the C-terminal amino acid attached peptidyl resin was deprotected by treating it twice with 20% (v/v) piperidine/DMF solution for 5 and 15 min.
- the resin was washed with DMF/DCM/DMF (6:6:6 time each).
- the Kaiser test on peptide resin aliquot upon completion of Fmoc-deprotection was positive.
- the ⁇ -amino group of lysine used as branching point or modification point was deprotected by using 2.5% hydrazine hydrate in DMF for 15 min ⁇ 2 and washed with DMF/DCM/DMF (6:6:6 time each).
- the ⁇ -carboxyl end of glutamic acid was attached to the ⁇ -amino group of Lys using Fmoc-Glu(OH)-OtBu with DIC/HOBt method (5 equivalent excess with respect to resin loading) in DMF.
- the mixture was rotated on a rotor at room temperature for 2 h.
- the resin was filtered and washed with DMF/DCM/DMF (6x30 ml each).
- the Fmoc group on the glutamic acid was de-protected by treating it twice with 20% (v/v) piperidine/DMF solution for 5 and 15 min (25 ml each). The resin was washed with DMF/ DCM/DMF (6:6:6 time each). A Kaiser test on peptide resin aliquot upon completion of Fmoc-deprotection was positive.
- a second Fmoc-Glu(OH)-OtBu used for the attachment to the free amino group of ⁇ -glutamic acid with DIC/HOBt method (5 equivalent excess with respect to resin loading) in DMF.
- the mixture was rotated on a rotor at room temperature for 2 h.
- Resin was filtered and washed with DMF/ DCM/DMF (6x30 ml each).
- the Fmoc group on the ⁇ -glutamic acid was de-protected by treating it twice with 20% (v/v) piperidine/DMF solution for 5 and 15 min (25 mL).
- the resin was washed with DMF/ DCM/DMF (6:6:6 time each).
- a Kaiser test on peptide resin aliquot upon completion of Fmoc-deprotection was positive.
- Palmitic acid and stearic acid attachment to side chains of glutamic acid To the free amino group of ⁇ -glutamic acid, palmitic acid or stearic acid (5 equiv.) dissolved in DMF was added and coupling was initiated by the addition of DIC (5 equiv.) and HOBt (5 equiv.) in DMF. The resin was washed with DMF/DCM/DMF (6:6:6 time each).
- a different route for the introduction of the lysine side chain is used, applying a prefunctionalized building block where the side chain is already attached to the lysine (e.g. (2S)-6-[[(4S)-5-tert-butoxy-4-[[(4S)-5-tert-butoxy-4-(hexadecanoylamino)-5-oxo-pentanoyl]amino]-5-oxo-pentanoyl]amino]-2-(9H-fluoren-9-ylmethoxycarbonylamino)hexanoic acid) as coupling partner in the peptide synthesis.
- a prefunctionalized building block where the side chain is already attached to the lysine e.g. (2S)-6-[[(4S)-5-tert-butoxy-4-[[(4S)-5-tert-butoxy-4-(hexadecanoylamino)-5-oxo-pentanoyl]a
- the crude peptides were purified either on an ⁇ kta Purifier System, a Jasco semiprep HPLC System or a Agilent 1100 HPLC system. Preparative RP-C18-HPLC columns of different sizes and with different flow rates were used depending on the amount of crude peptide to be purified. Acetonitrile + 0.1% TFA (B) and water + 0.1% TFA (A) were employed as eluents. Product-containing fractions were collected and lyophilized to obtain the purified product, typically as TFA salt.
- UPLC-UV was performed after 1 hour of gentle agitation from the supernatant, which was obtained after 15min of centrifugation at 2500 RCF (relative centrifugal acceleration).
- the solubility was determined by the comparison of the UV peak area of 2 ⁇ L-injection of a buffered sample diluted 1:10 with a standard curve of a reference peptide with known concentration.
- the different UV extinction coefficients of sample and reference peptide were calculated based on the different amino acid sequences and considered in the concentration calculation.
- Peptide solutions were filtered through 0.22 ⁇ M pore size and filled into aliquots under aseptic conditions. At starting point UPLC-UV was performed by injection of 2 ⁇ l of the undiluted sample.
- a monochromatic and coherent light beam (laser) is used to illuminate the liquid sample.
- Dynamic Light Scattering measures light scattered from particles (1nm ⁇ radius ⁇ 1 ⁇ m) that undergo Brownian motion. This motion is induced by collisions between the particles and solvent molecules that themselves are moving due to their thermal energy. The diffusional motion of the particles results in temporal fluctuations of the scattered light [ Pecora, R. Dynamic Light Scattering: Applications of Photon Correlation Spectroscopy, Plenum Press, 1985 ].
- the scattered light intensity fluctuations are recorded and transformed into an autocorrelation function.
- the diffusion coefficient D of the particles in solution can be derived.
- the diffusion coefficient is then used to calculate the hydrodynamic radius R h (or apparent Stokes radius) through the Stokes-Einstein equation assuming spherical particles. This calculation is defined in ISO 13321 and ISO 22412 [International Standard ISO13321 Methods for Determination of Particle Size Distribution Part 8: Photon Correlation Spectroscopy, International Organisation for Standardisation (ISO) 1996; International Standard ISO22412 Particle Size Analysis - Dynamic Light Scattering, International Organisation for Standardisation (ISO) 2008].
- the autocorrelation function is the sum of the exponential decays corresponding to each of the species.
- the temporal fluctuations of the scattered light can then be used to determine the size distribution profile of the particle fraction or family.
- the first order result is an intensity distribution of scattered light as a function of the particle size.
- the intensity distribution is naturally weighted according to the scattering intensity of each particle fraction or family.
- the particle scattering intensity is proportional to the square of the molecular weight.
- small amount of aggregates/agglomerates or presence or a larger particle species can dominate the intensity distribution.
- This distribution can be used as a sensitive detector for the presence of large material in the sample.
- the intensity distribution can be converted into a volume or mass distribution of the particle sizes using the Mie theory under certain assumptions. In contrast to the intensity distribution, the mass distribution is best used for comparative purposes and should never be considered absolute (due to the underlying assumptions).
- the DLS technique produces distributions with inherent peak broadening.
- the polydispersity index %Pd is a measure of the width of the particle size distribution and is calculated by standard methods described in ISO13321 and ISO22412 [International Standard ISO13321 Methods for Determination of Particle Size Distribution Part 8: Photon Correlation Spectroscopy, International Organisation for Standardisation (ISO) 1996; International Standard ISO22412 Particle Size Analysis - Dynamic Light Scattering, International Organisation for Standardisation (ISO) 2008].
- the DLS interaction parameter (k D ) is a measure to describe inter-particle interactions, where the particles are folded proteins or peptides [ Sandeep Yadav et al. (2009) J Pharm Sc, Vol 99(3), pp 1152-1168 ; Brian D. Connolly et al. (2012) Biophysical Journal Volume 103, pp 69-78 ].
- k D 2 B 22 M ⁇ k s ⁇ U
- the hydrodynamic radius R h and the diffusion constant D were determined as an average over triplicates. Both parameters were determined at different concentrations (e.g., R h1 and D 1 : 1 mg/ml and R h5 and D 5 : 5 mg/ml) in the same buffer system. The difference of these parameters between low and high peptide concentration is a surrogate for the DLS interaction parameter k D . R h5 ⁇ R h1 or D 5 > D 1 correspond to k D > 0 and therefore to repulsive inter-particle interactions that result in improved physical (or colloidal) stability.
- DLS Method A DLS measurements were performed on a W130i apparatus (Avid Nano Ltd, High Wycombe, UK) and using a low-volume disposable cuvette (UVette, Eppendorf AG, Hamburg, Germany). The data were processed with i-Size 3.0 provided by Avid Nano. Parameters of the particle size distribution were determined with non-negatively constrained least squares (NNLS) methods using DynaLS algorithms. Measurements were taken at 25°C with a 660nm laser light source and at an angle of 90°.
- NLS non-negatively constrained least squares
- DLS Method B DLS measurements were performed on a Nanosizer ZS (Malvern Instruments, Malvern, UK) and using disposible UV cuvettes (Brand macro , 2,5 mL and Brand semi-micro 1,5 mL, Brand GmbH + Co KG, Wertheim, Germany). The data were processed with Malvern Zetasizer software Version 7.10 or 7.01. Parameters of the particle size distribution were determined with non-negatively constrained least squares (NNLS) methods. Measurements were taken at 25°C with a 633nm laser light source in NIBS (Non-Invasive Back-Scatter) mode at an angle of 173°.
- NLS non-negatively constrained least squares
- DLS Method C DLS measurements were performed on a DynaPro Plate Reader II (Wyatt Technology, Santa Barbara, CA, US) and using one of the following black, low volume, and non-treated plates: polystyrene 384 assay plate with clear bottom (Corning, NY, US), polystyrene 96 assay plate with clear bottom (Corning, NY, US), cyclo olefin polymer (COP) 384 assay plate with clear bottom (Aurora, MT, US), or polystyrene 384 assay plate with clear bottom (Greiner Bio-One, Germany). The data were processed with the Dynamics software provided by Wyatt Technology. Parameters of the particle size distribution were determined with non-negatively constrained least squares (NNLS) methods using DynaLS algorithms. Measurements were taken at 25°C with an 830 nm laser light source at an angle of 158°.
- NLS non-negatively constrained least squares
- Thioflavin T is widely used to visualize and quantify the presence of misfolded protein aggregates.[ Biancalana et al. (2010) Biochimica et Biophysica Acta. 1804 (7): 1405-1412 .]. When it binds to fibrils, such as those in amyloid aggregates, the dye displays a distinct fluorescence signature [ Naiki et al. (1989)Anal. Biochem.177, 244-249 ; LeVine (1999) Methods. Enzymol. 309, 274-284 ]. The time course for fibril formation often follows the characteristic shape of a sigmoidal curve and can be separated into three regions: a lag phase, a fast growth phase, and a plateau phase.
- the typical fibril formation process starts with the lag phase in which the amount of partially folded peptide turned into fibrils is not significant enough to be detected.
- the lag-time corresponds to the time the critical mass of the nucleus is built. Afterwards, a drastic elongation phase follows and fibril concentration increases rapidly.
- Peptides were diluted in a buffer system to a final concentration of 3 mg/ml. 20 ⁇ L of a 10.1 mM ThT solution in H2O were added to 2 mL of peptide solution to receive a final concentration of 100 ⁇ M ThT. For each sample eight replicates were tested.
- Tht buffer system A 100 mM Acetate pH 4.5 including m-cresol (100 mM Natriumacetat trihydrat, pH adjustment using 2N CH3COOH, 2. 7 mg/mL m-cresol)
- Tht buffer system B 100 mM citrate buffer pH 6.0
- cAMP content of cells was determined using a kit from Cisbio Corp. (cat. no. 62AM4PEJ) based on HTRF (Homogenous Time Resolved Fluorescence).
- DMEM fetal bovine serum
- FBS fetal bovine serum
- test compound in assay buffer was added to the wells, followed by incubation for 30 minutes at room temperature.
- HTRF reagents diluted in lysis buffer (kit components)
- the plates were incubated for 1 hr, followed by measurement of the fluorescence ratio at 665 / 616 nm.
- In vitro potency of agonists was quantified by determining the concentrations that caused 50% activation of maximal response (EC50).
- mice were dosed 1 mg/kg subcutaneously (s.c.). The mice were sacrified and blood samples were collected after 0.25, 0.5, 1, 2, 4, 8, 16 and 24 hours post application. Plasma samples were analyzed after protein precipitation via liquid chromatography mass spectrometry (LC/MS). PK parameters and half-life were calculated using WinonLin Version 5.2.1 (non-compartment model).
- mice Female Göttinger minipigs were dosed 0.05 mg/kg, 0.075 mg/kg or 0.1 mg/kg subcutaneously (s.c.). Blood samples were collected after 0.25, 0.5, 1, 2, 4, 8, 24, 32, 48, 56 and 72 hours post application. Plasma samples were analyzed after protein precipitation via liquid chromatography mass spectrometry (LC/MS). PK parameters and half-life were calculated using WinonLin Version 5.2.1 (non-compartment model).
- mice Female C57BL/6NHsd mice were ordered group housed from Envigo RMS Inc., shipped group housed and remained group housed with shipped cage mates in shoebox caging with wood chip bedding until day 38 of the predose phase. At the study start mice were between 25-26 weeks old.
- mice were housed under vivarium conditions that included a 12 h light/dark cycle (light phase 04:00 AM - 4:00 PM), room temperatures between 23 - 26°C and a relative humidity between 30 - 70%. All animals had free access to water and a high fat diet (TD97366) for 16 weeks prior to pharmacological intervention (dosing phase).
- Feed was replaced with fresh feed weekly until and for the last time on day 38 of the predose phase. During the subsequent dosing phase, approximately 50% of the remaining feed were removed, replaced with fresh feed, and pellets were mixed evenly once per week.
- test article On day 37 of the predose phase, the test article was diluted with PBS to a concentration of 100 ⁇ g/mL and aliquots of this stock solution were stored at approximately ⁇ -60°C. Stock aliquots were thawed for weekly use and thereafter stored in a refrigerator at approximately 4°C. The injected test article solution was prepared fresh once on each dosing day by diluting stock solution with PBS to achieve the desired concentration.
- mice were treated twice daily with a s.c. injection of PBS-vehicle or the test article for 28 days.
- the morning dosing was initiated and completed between 06:00 and 07:30 AM and the afternoon dosing between 2:00 and 3:30 PM.
- On day 28 of the dosing phase only the morning dose was administered.
- the applied volume was 5 ml/kg and the dose was adjusted to the most recent body mass recording of each individual.
- mice Female healthy, lean BKS.Cg-(lean)/OlaHsd and diabetes-prone, obese BKS.Cg-+Lepr db /+Lepr db /OlaHsd mice were ordered group housed from Envigo RMS Inc., shipped group housed and remained group housed in shoebox caging with wood chip bedding until day 15 of the predose phase. At the study start mice were approximately 12 weeks old.
- mice were housed under vivarium conditions including a 12 h light/dark cycle (light phase 04:00 AM - 4:00 PM), room temperatures between 23 - 26°C and a relative humidity between 30 - 70%. All animals had free access to water and Purina Fomulab Diet 5008.
- test article Prior to day 1 of the dosing phase, the test article was diluted with Phosphate Buffered Saline (PBS, Gibco, without CaCl 2 and MgCl 2 ) to a concentration of 1 mg/mL and aliquots of this stock solution were stored at approximately ⁇ -60°C. On day 1 of the dosing phase the stock aliquot was thawed and the injected test article solution was prepared fresh by diluting it with PBS to achieve the desired concentration.
- PBS Phosphate Buffered Saline
- mice On Day 1 of the dosing phase db/db mice were either treated once with a s.c. injection of PBS-vehicle or 30 ⁇ g/kg test article. The lean reference group was treated once with a s.c. injection of PBS-vehicle. The dosing was initiated and completed between 08:00 and 10:00 AM. The applied volume was 5 ml/kg and the dose was adjusted to the most recent body mass recording of each individual.
- Palm-gGlu-gGlu-OSu was coupled to the liberated amino-group employing DIPEA as base.
- the peptide was cleaved from the resin with King's cocktail ( D. S. King, C. G. Fields, G. B. Fields, Int. J. Peptide Protein Res. 1990, 36, 255-266 ).
- the crude product was purified via preparative HPLC on a Waters column (Sunfire Prep C18 ODB 5 ⁇ m 50x150mm) using an acetonitrile/water gradient (both buffers with 0,1% TFA).
- the purified peptide was analysed by LCMS (Method B).
- the solid phase synthesis as described in Methods was carried out on Novabiochem Rink-Amide resin (4-(2',4'-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucylaminomethyl resin), 100-200 mesh, loading of 0.43 mmol/g.
- the Fmoc-synthesis strategy was applied with HBTU/DIPEA-activation. In position 14 Fmoc-Lys(Mmt)-OH and in position 1 Boc-His(Trt)-OH were used in the solid phase synthesis protocol.
- the Mmt-group was cleaved from the peptide on resin as described in the Methods.
- Palm-gGlu-gGlu-OSu was coupled to the liberated amino-group employing DIPEA as base.
- the peptide was cleaved from the resin with King's cocktail ( D. S. King, C. G. Fields, G. B. Fields, Int. J. Peptide Protein Res. 1990, 36, 255-266 ).
- the crude product was purified via preparative HPLC on a Waters column (Sunfire Prep C18 OBD 5 ⁇ m 50x150mm) using an acetonitrile/water gradient (both buffers with 0,1% TFA).
- the purified peptide was analysed by LCMS (Method B).
- the solid phase synthesis as described in Methods was carried out on Novabiochem Rink-Amide resin (4-(2',4'-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucylaminomethyl resin), 100-200 mesh, loading of 0.43 mmol/g.
- the Fmoc-synthesis strategy was applied with HBTU/DIPEA-activation. In position 14 Fmoc-Lys(Mmt)-OH and in position 1 Boc-His(Trt)-OH were used in the solid phase synthesis protocol.
- the Mmt-group was cleaved from the peptide on resin as described in the Methods.
- Palm-gGlu-gGlu-OSu was coupled to the liberated amino-group employing DIPEA as base.
- the peptide was cleaved from the resin with King's cocktail ( D. S. King, C. G. Fields, G. B. Fields, Int. J. Peptide Protein Res. 1990, 36, 255-266 ).
- the crude product was purified via preparative HPLC on a Waters column (Sunfire Prep C18 OBD 5 ⁇ m 50x150mm) using an acetonitrile/water gradient (both buffers with 0,1% TFA).
- the purified peptide was analysed by LCMS (Method B).
- Table 3 list of synthesized peptides and comparison of calculated vs. found molecular weight SEQ ID NO calc. Mass found mass Monoisotopic or average mass Retention time (min) 6 4839.7 4839.7 monoisotopic 9.824 7 4853.7 4853.7 monoisotopic 9.935 8 4880.6 4880.6 monoisotopic 9.585 9 4840.6 4840.6 monoisotopic 10.471 10 4854.6 4854.7 monoisotopic 10.64 11 4894.6 4849.6 monoisotopic 9.828 12 4879.7 4879.7 monoisotopic 9.490 13 4893.7 4893.7 monoisotopic 9.690 14 4710.6 4710.7 monoisotopic 9.435 15 4738.7 4783.7 monoisotopic 10.528 16 5024.7 5024.7 monoisotopic 9.137 17 5038.8 5038.8 monoisotopic 9.286 18 5025.7 5025.7 monois
- the hydrodynamic radius radius R h of peptide samples was determined at different peptide concentrations (1 mg/ml and 5 mg/ml) in DLS buffer system A using DLS method C as described in Methods as surrogate for the DLS interaction parameter k D .
- the results are given in Table 6.
- Example 7 Stability was assessed in the ThT assay.
- Lag time in hours in Thioflavin T (ThT) assay of peptide samples was determined in Tht buffer system A as described in Methods. The results are given in Table 7.
- Table 7 Lag time in hours in Thioflavin T (ThT) assay SEQ ID NO Increase in FI at pH 4.5 Lag time before increase [h] 6 NO >45 7 NO >45 8 NO >45 9 NO >45 10 NO >45 11 NO >45 12 NO >45 13 NO >45 16 NO >45 17 NO >45 18 NO >45 19 NO >45 20 NO >45 21 NO >45 22 NO >45 23 NO >45
- Example 8 In vitro data on human GLP-1, glucagon and GIP receptor
- Potencies of peptidic compounds at the GLP-1, glucagon and GIP receptors were determined by exposing cells expressing human glucagon receptor (hGlucagon R), human GIP receptor (hGIP-R) or human GLP-1 receptor (hGLP-1 R) to the listed compounds at increasing concentrations and measuring the formed cAMP as described in Methods.
- Table 8 EC50 values of exendin-4 derivatives at human GLP-1, Glucagon and GIP receptors (indicated in pM) SEQ ID NO EC50 hGLP-1R EC50 hGlucagon R EC50 hGIP R 6 2.8 16.4 7.9 7 4.0 21.8 14.2 8 2.2 32.6 5.6 9 2.6 24.7 5.6 10 2.4 26.1 5.4 11 2.3 22.4 3.5 12 2.7 22.0 15.8 13 3.8 25.8 20.4 14 5.7 31.6 18.2 15 5.7 15.6 26.1 16 1.3 18.6 7.5 17 1.8 22.0 11.4 18 1.7 46.6 5.6 19 1.9 52.2 7.9 20 2.4 44.0 12.7 21 4.2 69.9 24.6 22 2.1 108.0 6.0 23 1.0 64.3 2.0
- mice Lean and diet-induced obese, 25-26 weeks old, female C57BL/6NHsd mice were treated twice daily with a s.c. injection of PBS, 30 ⁇ g/kg SEQ ID NO: 6, or 30 ⁇ g/kg SEQ ID NO: 7 for 28 days.
- the morning dosing was initiated and completed between 06:00 and 07:30 AM and the afternoon dosing between 14:00 and 15:30 PM.
- the applied volume was 5 ml/kg and the dose was adjusted to the most recent body mass recording of each individual.
- Glucose measurements were performed in whole blood and in duplicate or triplicate using Aviva glucometers. Both, 30 ⁇ g/kg SEQ ID NO: 6 and 30 ⁇ g/kg SEQ ID NO: 7 mediated a comparable decrease in blood glucose concentrations below concentrations observed in DIO control mice during the 24 hour blood glucose profile ( Figure 2 ).
- mice were treated twice daily with either a s.c. injection of PBS-vehicle, 30 ⁇ g/kg SEQ ID NO: 6, or 30 ⁇ g/kg SEQ ID NO: 7.
- mice were treated twice daily with either a s.c. injection of PBS-vehicle, 30 ⁇ g/kg SEQ ID NO: 6, or 30 ⁇ g/kg SEQ ID NO: 7.
- mice were euthanized 4 hours after the morning dose and livers were collected.
- mice Female, 12 weeks old, healthy, lean BKS.Cg-(lean)/OlaHsd or diabetes-prone, obese BKS.Cg-+Leprdb/+Leprdb/OlaHsd mice were treated once with a s.c. injection of PBS, 30 ⁇ g/kg SEQ ID NO: 6 or 30 ⁇ g/kg SEQ ID NO: 7. The dosing was initiated and completed between 08:00 and 10:00 AM. The applied volume was 5 ml/kg and the dose was adjusted to the most recent body mass recording of each individual. Diabetic db/db mice were HbA1c- and body mass-matched. The lean reference group was treated once with a s.c. injection of PBS-vehicle.
- mice had unlimited access to water and feed during the experiment.
- On day 1 of the dosing phase approximately 5 ⁇ L of blood were collected via tail clips at minute -30 and 0 prior to any other inlife activities.
- At minute 0 mice received a s.c. dose of either PBS-vehicle, 30 ⁇ g/kg SEQ ID NO: 6 or SEQ ID NO: 7.
- Further blood samples were harvested at minute 15, 30, 60, 90, 120, 150, 180, 240, 360, and 480 post-dose.
- Glucose measurements were performed in whole blood using AlphaTRAK glucometers. If the glucose concentrations of two measurements differed by more than 20 mg/dL a third value was recorded.
- the Area Under the Curve (AUC) for blood glucose was calculated via the trapezoid method and for the duration of the 24 post-dose hours.
- SEQ ID NO: 6 or SEQ ID NO: 7 treated animals exhibited a comparable, acute decrease in blood glucose concentrations and reached lowest levels approximately 8 hours post dose ( Figure 10 ). Twentyfour hours post-dose mean blood glucose concentrations of all treated animals were at or close to baseline ( Figure 10 ). Single treatment of diabetic db/db mice with 30 ⁇ g/kg SEQ ID NO: 6 or 30 ⁇ g/kg SEQ ID NO: 7 resulted in a statistically significant reduction in the blood glucose AUC compared to the Diabetic-Vehicle group (One-Way ANOVA and Tukey Test, Figure 11 , Table 10).
- mice Lean and diet-induced obese, 25-26 weeks old, female C57BL/6NHsd mice were treated twice daily with a s.c. injection of PBS, 30 ⁇ g/kg SEQ ID NO: 8, 30 ⁇ g/kg SEQ ID NO: 9, or 30 ⁇ g/kg SEQ ID NO: 10 for 28 days.
- the morning dosing was initiated and completed between 06:00 and 07:30 AM and the afternoon dosing between 14:00 and 15:30 PM.
- the applied volume was 5 ml/kg and the dose was adjusted to the most recent body mass recording of each individual.
- mice were treated twice daily with either a s.c. injection of PBS-vehicle, 30 ⁇ g/kg SEQ ID NO: 8, 30 ⁇ g/kg SEQ ID NO: 9, or 30 ⁇ g/kg SEQ ID NO: 10.
- mice were treated twice daily with either a s.c. injection of PBS-vehicle, 30 ⁇ g/kg SEQ ID NO: 8, 30 ⁇ g/kg SEQ ID NO: 9, or 30 ⁇ g/kg SEQ ID NO: 10.
- Chronic, twice daily treatment with SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO resulted in a statistically significantly reduction in whole body fat mass within the 28 days compared to the DIO-Vehicle group (One-Way ANOVA and Tukey Test, Figure 15 , Table 11).
- mice were euthanized 4 hours after the morning dose and livers were collected.
- DIO-Vehicle Whole body fat mass change (g) 2.51 ⁇ 0.65 -6.65 ⁇ 0.38 P ⁇ 0.001 vs. -5.29 ⁇ 2.32 P ⁇ 0.001 vs. -6.48 ⁇ 0.90 P ⁇ 0.001 vs. DIO-Vehicle DIO-Vehicle DIO-Vehicle Terminal liver mass (g) +1.80 ⁇ 0.07 +1.08 ⁇ 0.03 P ⁇ 0.001 vs. DIO-Vehicle +1.11 ⁇ 0.06 P ⁇ 0.001 vs. DIO-Vehicle +1.07 ⁇ 0.04 P ⁇ 0.001 vs.
- mice Female, 12 weeks old, healthy, lean BKS.Cg-(lean)/OlaHsd or diabetes-prone, obese BKS.Cg-+Lepr db /+Lepr db /OlaHsd mice were treated once with a s.c. injection of PBS or30 ⁇ g/kg SEQ ID NO: 13. The dosing was initiated and completed between 08:00 and 10:00 AM. The applied volume was 5 ml/kg and the dose was adjusted to the most recent body mass recording of each individual. Diabetic db/db mice were HbA1c- and body mass-matched. The lean reference group was treated once with a s.c. injection of PBS-vehicle.
- mice had unlimited access to water and feed during the experiment.
- On day 1 of the dosing phase approximately 5 ⁇ L of blood were collected via tail clips at minute -30 and 0 prior to any other inlife activities.
- At minute 0 mice received a s.c. dose of either PBS-vehicle or 30 ⁇ g/kg SEQ ID NO: 13.
- Further blood samples were harvested at minute 15, 30, 60, 90, 120, 150, 180, 240, 360, and 480 post-dose.
- Glucose measurements were performed in whole blood using AlphaTRAK glucometers. If the glucose concentrations of two measurements differed by more than 20 mg/dL a third value was recorded.
- the Area Under the Curve (AUC) for blood glucose was calculated via the trapezoid method and for the duration of the 24 post-dose hours.
- SEQ ID NO: 13 treated animals exhibited an acute decrease in blood glucose concentrations and reached lowest levels approximately 8 hours post dose ( Figure 20 ). Twentyfour hours post-dose mean blood glucose concentrations of SEQ ID NO: 13 treated animals were close to baseline ( Figure 20 ).
- Single treatment of diabetic db/db mice with 30 ⁇ g/kg SEQ ID NO: 13 resulted in a statistically significant reduction in the blood glucose AUC compared to the Diabetic-Vehicle group (One-Way ANOVA and Tukey Test, Figure 21 , Table 12).
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Gastroenterology & Hepatology (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Toxicology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Obesity (AREA)
- Vascular Medicine (AREA)
- Immunology (AREA)
- Emergency Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
- The present invention relates to new compounds which are trigonal GLP-1 / glucagon / GIP receptor agonists and their medical use, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as for reduction of excess food intake. The compounds of the invention are structurally derived from exendin-4 and show high solubility and stability under acidic conditions in the presence of antimicrobial preservatives like m-cresol or phenol which makes them especially suited for combinations with other antidiabetic compounds.
- Bhat et al (Diabetologia 2013, 56, 1417-1424), Bhat et al. (Biochem Pharmacol. 2013, 85, 1655-62), Gault et al. (J Biol Chem. 2013, 288, 35581-91) as well as Finan et al. (Nat Med. 2015, 21, 27-36) described trigonal agonists of the glucagon-like peptide-1 (GLP-1), the glucagon and the glucose-dependent insulinotropic polypeptide (GIP) receptors, e.g. by combining the actions of GLP-1, glucagon and GIP in one molecule, which leads to a therapeutic principle with anti-diabetic action and a pronounced weight lowering effect superior to pure GLP-1 agonists, among others due to glucagon-receptor mediated increased satiety and energy expenditure as well as GIP receptor mediated increased insulin secretion.
- The amino acid sequence of GLP-1 (7-36)-amide is shown as SEQ ID NO: 1.
HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2 - Liraglutide is a marketed chemically modified GLP-1 analog in which, among other modifications, a fatty acid is linked to a lysine in
position 20 leading to a prolonged duration of action (Drucker et al, Nat. Rev. Drug Disc. 2010, 9, 267-268; Buse et al., Lancet 2009, 374, 39-47). - The amino acid sequence of Liraglutide is shown as SEQ ID NO: 2.
HAEGTFTSDVSSYLEGQAAK((S)-4-Carboxy-4-hexadecanoylamino-butyryl) EFIAWLVRGRG-OH - Glucagon is a 29-amino acid peptide which is released into the bloodstream when circulating glucose is low. Glucagon's amino acid sequence is shown as SEQ ID NO: 3.
HSQGTFTSDYSKYLDSRRAQDFVQWLMNT-OH - During hypoglycemia, when blood glucose levels drop below normal, glucagon signals the liver to break down glycogen and release glucose, causing an increase of blood glucose levels to reach a normal level. Recent publications suggest that glucagon has in addition beneficial effects on reduction of body fat mass, reduction of food intake, and increase of energy expenditure (Heppner et al., Physiology & Behavior 2010, 100, 545-548).
- GIP (glucose-dependent insulinotropic polypeptide) is a 42 amino acid peptide that is released from intestinal K-cells following food intake. GIP and GLP-1 are the two gut enteroendocrine cell-derived hormones accounting for the incretin effect, which accounts for over 70% of the insulin response to an oral glucose challenge (Baggio et al. Gastroenterology 2007, 132, 2131-2157).
- GIP's amino acid sequence is shown as SEQ ID NO: 5.
YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ-OH - Peptides which are based on the structures of GLP-1 or glucagon, and bind and activate the GLP-1, the glucagon and the GIP receptor have been described in patent applications
WO 2010/011439 ,WO 2010/148089 ,WO 2012/088116 ,WO 2013/192129 ,WO 2013/192130 ,WO 2014/049610 andWO 2015/067716 . Further trispecific agonists based on exendin-4 have been described inWO 2014/096145 ,WO 2015/086731 ,WO 2015/086732 ,WO 2015/086733 ,WO2015/155141 , andPCT/EP2016/063332 - Peptides which bind and activate both the GIP and the GLP-1 receptor designed as analogues of exendin-4 and substituted with a fatty acid side chain are described in patent applications
WO 2014/096145 A1 ,WO 2014/096150 A1 ,WO 2014/096149 A1 , andWO 2014/096148 A1 . - Exendin-4 is a 39 amino acid peptide which is produced by the salivary glands of the Gila monster (Heloderma suspectum. Exendin-4 is an activator of the GLP-1 receptor, whereas it shows low activation of the GIP receptor and does not activate the glucagon receptor (see Table 1).
Table 1: Potencies of exendin-4 at human GLP-1, GIP and Glucagon receptors (indicated in pM) at increasing concentrations and measuring the formed cAMP as described in Methods. SEQ ID NO: peptide EC50 hGLP-1 R [pM] EC50 hGIP R [pM] EC50 hGlucagon R [pM] 4 exendin-4 0.4 12500.0 >10000000 - The amino acid sequence of exendin-4 is shown as SEQ ID NO: 4.
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2 - Exendin-4 shares many of the glucoregulatory actions observed with GLP-1. Clinical and nonclinical studies have shown that exendin-4 has several beneficial antidiabetic properties including a glucose dependent enhancement in insulin synthesis and secretion, glucose dependent suppression of glucagon secretion, slowing down gastric emptying, reduction of food intake and body weight, and an increase in beta-cell mass and markers of beta cell function.
- These effects may be beneficial not only for diabetics but also for patients suffering from obesity. Patients with obesity have a higher risk of getting diabetes, hypertension, hyperlipidemia, cardiovascular and musculoskeletal diseases.
- Relative to GLP-1, exendin-4 is resistant to cleavage by dipeptidyl peptidase-4 (DPP4) resulting in a longer half-life and duration of action in vivo (Eng J., Diabetes, 1996, 45 (Suppl 2):152A (abstract 554)).
- Exendin-4 was also shown to be much more stable towards degradation by neutral endopeptidase (NEP), when compared to GLP-1, glucagon or oxyntomodulin (Druce et al., Endocrinology, 2009, 150(4), 1712-1722). Nevertheless, exendin-4 is chemically labile due to methionine oxidation in position 14 (Hargrove et al., Regul. Pept., 2007, 141, 113-119) as well as deamidation and isomerization of asparagine in position 28 (
WO 2004/035623 ). -
Bloom et al. (WO 2006/134340 ) disclose that peptides which bind and activate both the glucagon and the GLP-1 receptor can be constructed as hybrid molecules from glucagon and exendin-4, where the N-terminal part (e.g. residues 1-14 or 1-24) originates from glucagon and the C-terminal part (e.g. residues 15-39 or 25-39) originates from exendin-4. Such peptides comprise glucagon's amino acid motif YSKY in position 10-13. Krstenansky et al (Biochemistry, 1986, 25, 3833-3839) show the importance of these residues 10-13 of glucagon for its receptor interactions and activation of adenylate cyclase. Compared to GLP-1, glucagon and oxyntomodulin, exendin-4 has beneficial physicochemical properties, such as solubility and stability in solution and under physiological conditions (including enzymatic stability towards degradation by enzymes, such as DPP4 or NEP), which results in a longer duration of action in vivo. - Nevertheless, also exendin-4 has been shown to be chemically labile due to methionine oxidation in
position 14 as well as deamidation and isomerization of asparagine inposition 28. Stability might be further improved by substitution of methionine atposition 14 and the avoidance of sequences that are known to be prone to degradation via aspartimide formation, especially Asp-Gly or Asn-Gly atpositions 28 and 29. -
WO 2015/155141 A1 provides exendin-4 analogues with only 4 or 5 amino acid modifications compared to native exendin-4 which potently activate not only the GLP-1 receptor but also the glucagon receptor and optionally the GIP receptor. -
WO 2014/096145 A1 similarly relates to exendin-4 analogues which potently activate the GLP and the GIP receptor and optionally the glucagon receptor. In both applications, the general formula differs from the present formula I. -
WO 2013/192129 A1 provides peptides that are GIP agonist peptides contemplated for use in treating subjects in need thereof, e.g. with diabetes and obesity. -
WO 2015/067716 A1 concerns glucagon/GLP-1/GIP triple agonists, which comprise one or more substitutions as compared to wild-type glucagon and which may have the property of an altered, preferably increased GIP and GLP-1 receptor activity. -
WO 2016/198624 A1 relates to exendin-4 derivatives, which in addition to the agonistic activity at the GLP-1 receptor of native exendin-4 show agonistic activity at the glucagon receptor and the GIP receptor and have, among others, the following modifications: atposition 2 an alpha-aminoisobutyric acid, at position 3 a histidine, at position 17 a glutamine, at position 18 a leucine and at position 27 an isoleucine. - In the compounds of the present invention several of the underlying residues are different from glucagon and the peptides described in
WO 2006/134340 . In particular residues Tyr10 and Tyr13, which are known to contribute to the fibrillation of glucagon (JS Pedersen et al., Biochemistry, 2006, 45, 14503-14512) are replaced by Leu. This replacement, especially in combination with isoleucine in position 23 and glutamate inposition 24, leads to exendin-4 derivatives with potentially improved biophysical properties as solubility or aggregation behaviour in solution. The non-conservative replacement of an aromatic amino acid with an aliphatic amino acid inposition 13 of an exendin-4 analogue leads to peptides with high activity on both the glucagon and the GIP receptor, keeping their activity on the GLP-1 receptor. - Native exendin-4 is a pure GLP-1 receptor agonist without activity on the glucagon receptor and low activity on the GIP receptor. The compounds of the invention are based on the structure of native exendin-4 but differing at fourteen or more positions as compared to SEQ ID NO: 4 wherein the differences contribute to the enhancement of the agonistic activity at the glucagon receptor and the GIP receptor. Among other substitutions - methionine at
position 14 is replaced by an amino acid carrying an -NH2 group in the side-chain, which is further substituted by a lipophilic residue (e.g. a fatty acid combined with a linker). Further the replacement of the exendin-4 amino acids atpositions position 13, a Gln in position 19, an Aib or Lys amino acid inposition 20, an Aib in position 34, Pro at position 32 and Lys atposition 35 and 39 leads to high activity on both the glucagon as well as the GIP receptor while keeping the high activity on the GLP-1 receptor. These peptides also show high chemical stability, solubility and physical stability at acidic pH values, such as pH4.5. -
- X14
- represents an amino acid residue with a functionalized -NH2 side chain group, selected from the group consisting of Lys, Orn, Dab, or Dap, wherein the -NH2 side chain group is functionalized by -Z-C(O)-R5, wherein Z represents a linker in all stereoisomeric forms and R5 is a moiety comprising up to 50 carbon atoms and heteroatoms selected from N and O,
- X16
- represents an amino acid residue selected from Lys and Glu,
- X29
- represents an amino acid residue selected from D-Ala and Gly,
- X31
- represents an amino acid residue selected from His and Pro,
- R1
- is NH2 or OH,
- The compounds of the invention are GLP-1, glucagon and GIP receptor agonists as determined by the observation that they are capable of stimulating intracellular cAMP formation in the assay system described in Methods.
- According to another embodiment the compounds of the invention, particularly with a lysine at
position 14 which is further substituted with a lipophilic residue, exhibit at least a relative activity of 0.1% (i.e. EC50 < 700 pM), more preferably of 1% (i.e. EC50 < 70 pM), more preferably of 5% (i.e. EC50 < 14 pM) and even more preferably of 10% (i.e. EC50 < 7 pM) compared to that of GLP-1(7-36)amide at the GLP-1 receptor. Furthermore, the compounds of the invention exhibit at least a relative activity of 0.1% (i.e. EC50 < 500 pM), more preferably of 0.25% (i.e. EC50 < 200 pM), more preferably of 0,4% (<125 pM) and even more preferably of 1% (i.e. EC50 < 50 pM) compared to that of natural glucagon at the glucagon receptor. Furthermore, the compounds of the invention exhibit at least a relative activity of 0.1% (i.e. EC50 < 400 pM), more preferably of 0.4% (i.e. EC50 < 100 pM), more preferably of 1% (<40 pM) and even more preferably of 2% (i.e. EC50 < 20 pM) compared to that of natural GIP at the GIP receptor. - The term "activity" as used herein preferably refers to the capability of a compound to activate the human GLP-1 receptor, the human glucagon receptor and the human GIP receptor. More preferably the term "activity" as used herein refers to the capability of a compound to stimulate intracellular cAMP formation. The term "relative activity" as used herein is understood to refer to the capability of a compound to activate a receptor in a certain ratio as compared to another receptor agonist or as compared to another receptor. The activation of the receptors by the agonists (e.g. by measuring the cAMP level) is determined as described herein, e.g. as described in the examples.
- The compounds of the invention preferably have an EC50 for hGLP-1 receptor of 450 pM or less, preferably of 200 pM or less, more preferably of 100 pM or less, more preferably of 50 pM or less, more preferably of 25 pM or less, more preferably of 10 pM or less, more preferably of 8 pM or less, and more preferably of 5 pM or less and an EC50 for hGlucagon receptor of 450 pM or less, preferably of 200 pM or less, more preferably of 100 pM or less, more preferably of 50 pM or less, and an EC50 for hGIP receptor of 450 pM or less, preferably of 200 pM or less, more preferably of 100 pM or less, more preferably of 50 pM or less, more preferably of 25 pM or less. The EC50 for the hGLP-1 receptor, the hGlucagon receptor and the hGIP receptor may be determined as described in the Methods herein and as used to generate the results described in the examples.
- Compounds of the formula I particularly those with a lysine at
position 14 which is further substituted with a lipophilic residue, showed increased glucagon receptor activation compared to derivatives having the original methionine (from exendin-4) or leucine at position 14 (see alsoWO2014/056872 ). Furthermore, oxidation (in vitro or in vivo) of methionine is not possible anymore. - The compounds of formula I do not only show high activity on the glucagon receptor but as well on the GIP receptor. The additional high activity on the GIP receptor is intended for enhanced efficacy on blood glucose control compared to pure GLP-1 receptor agonism and to reduce the probability of GLP-1 related side effects like gastrointestinal distress as the contribution of the GLP-1 part can be reduced. The additional GIP receptor activity is also intended to counterbalance a potential glucose increase by glucagon receptor activation therefore allowing higher glucagon receptor activity as observed in compounds of formula I (Finan et al. Nat Med. 2015, 21, 27-36).
- In one embodiment the compounds of the invention have a high solubility at acidic and/or physiological pH values in the presence of an antimicrobial preservative like phenol or m-cresol, e.g., at an acidity range from
pH 4 to 5, especially pH 4.5 and/or a more physiological range frompH 6 to 8, especially at pH 7.4 at 25°C or 40°C, in another embodiment at least 1 mg/ml and in a particular embodiment at least 5 mg/ml. - Furthermore, the compounds of the invention preferably have a high stability when stored in solution in the presence of an antimicrobial preservative like phenol or m-cresol. Preferred assay conditions for determining the stability is storage for 28 days at 25°C or 40°C in solution at an acidity range from
pH 4 to 5, especially pH 4.5. The stability of peptide is determined by chromatographic analyses as described in the Methods. Preferably, after 28 days at 40°C in solution at pH 4.5 the purity loss is no more than 20%, more preferably no more than 15%, more preferably no more than 12% and even more preferably no more than 10%. - In one embodiment the compounds of the invention show a hydrodynamic radius Rh of 5 nm or less at concentrations of ≥ 1 mg/ml in the presence of an antimicrobial preservative like phenol or m-cresol, e.g., at an acidity range from
pH 4 to 5 at 25°C, especially pH 4.5 at 25°C as assayed by dynamic light scattering as described in Methods. - In one embodiment the compounds of the invention do not show an increase in fluorecense intensity with Thioflavin T as fluorescence probe at concentrations of 3 mg/ml in the presence of an antimicrobial preservative like phenol or m-cresol, e.g., at an acidity range from
pH 4 to 5, especially pH 4.5 at 37°C over 5 hours, more preferably over 10 hours, more preferably over 20 hours, more preferably over 30 hours, more preferably over 40 hours and even more preferably over 45 hours as assayed by the Tht assay as described in Methods. - In one embodiment the compounds of this invention are more resistant to cleavage by neutral endopeptidase (NEP) and dipeptidyl peptidase-4 (DPP4), resulting in a longer half-life and duration of action in vivo, when compared with native GLP-1 and glucagon.
- In one embodiment the compounds of the present invention comprise a peptide moiety which is a linear sequence of 39 amino carboxylic acids, particularly α-amino carboxylic acids linked by peptide, i.e. carboxamide bonds.
- In one embodiment, R1 is NH2.
- Specific preferred examples for -Z-C(O)-R5 groups are listed in the following Table 2, which are selected from (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl, (4S)-Carboxy- [2-(2-{2-[(4R)-5-carboxy-4-hexadecanoylamino-pentanoylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl , (4S)-Carboxy- [2-(2-{2-[(4R)-5-carboxy-4-hexadecanoylamino-pentanoylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl , (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-.
- Further preferred are stereoisomers, particularly enantiomers of these groups, either S- or R-enantiomers. The term "R" in Table 2 is intended to mean the attachment site of -Z-C(O)-R5 at the peptide back bone, for example the epsilon-amino group of Lys.
Table 2 Structure / IUPAC name gGlu-Stea gGlu-Palm gGlu-gGlu-Palm gGlu-gGlu-AEEAc-Palm gGlu-AEEAc-gAAA-Palm AEEAc-AEEAc-gGlu-Palm AEEAc-AEEAc-gGlu-Stea AEEAc-AEEAc-AEEAc-Stea - A further embodiment relates to compounds of formula I, wherein
- X14 represents Lys wherein the -NH2 side chain group is functionalized with a group -Z-C(O)R5 , wherein
- Z represents a group selected from gGlu, gGlu-gGlu, gGlu-AEEAc-gAAA-, gGlu-gGlu-AEEAc, AEEAc-AEEAc-gGlu and AEEAc-AEEAc-AEEAc; and R5 represents a group selected from pentadecanyl or heptadecanyl.
- A further embodiment relates to compounds of formula I, wherein
- X14 represents Lys wherein the -NH2 side chain group is functionalized with a group -Z-C(O)R5 , wherein
- Z represents a group selected from gGlu, gGlu-gGlu, gGlu-AEEAc-gAAA- and gGlu-gGlu-AEEAc; and
- R5 represents a group selected from pentadecanyl or heptadecanyl.
- A further embodiment relates to compounds of formula I, wherein
- X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-, R1 represents NH2,
- or a salt or solvate thereof.
- A further embodiment relates to compounds of formula I, wherein
- X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,
- R1 represents NH2,
- or a salt or solvate thereof.
- A further embodiment relates to compounds of formula I, wherein
- X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-
- 4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,
- X16 represents an amino acid residue selected from Glu and Lys,
- X29 represents an amino acid residue selected from D-Ala and Gly,
- X31 represents an amino acid residue selected from His and Pro,
- R1 represents NH2,
- or a salt or solvate thereof.
- A further embodiment relates to compounds of formula I, wherein
- X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-
- 4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,
- X16 represents an amino acid residue selected from Glu and Lys,
- X29 represents Gly,
- X31 represents an amino acid residue selected from His and Pro,
- R1 represents NH2,
- or a salt or solvate thereof.
- A further embodiment relates to compounds of formula I, wherein
- X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-
- 4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (S)-
- 4-Carboxy-4-octadecanoylamino-butyryl-,
- X16 represents Glu,
- X29 represents an amino acid residue selected from D-Ala and Gly,
- X31 represents His,
- R1 represents NH2,
- or a salt or solvate thereof.
- A further embodiment relates to compounds of formula I, wherein
- X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-
- 4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (S)-
- 4-Carboxy-4-octadecanoylamino-butyryl-,
- X16 represents Glu,
- X29 represents Gly,
- X31 represents an amino acid residue selected from His and Pro,
- R1 represents NH2,
- or a salt or solvate thereof.
- A further embodiment relates to compounds of formula I, wherein
- X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-
- 4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (S)-
- 4-Carboxy-4-octadecanoylamino-butyryl-,
- X16 represents Lys,
- X29 represents an amino acid residue selected from D-Ala and Gly,
- X31 represents an amino acid residue selected from His and Pro,
- R1 represents NH2,
- or a salt or solvate thereof.
- A further embodiment relates to compounds of formula I, wherein
- X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-
- 4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (S)-
- 4-Carboxy-4-octadecanoylamino-butyryl-,
- X16 represents an amino acid residue selected from Glu and Lys,
- X29 represents an amino acid residue selected from D-Ala and Gly,
- X31 represents Pro,
- R1 represents NH2,
- or a salt or solvate thereof.
- A further embodiment relates to compounds of formula I, wherein
- X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-
- 4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (S)-
- 4-Carboxy-4-octadecanoylamino-butyryl-,
- X16 represents Lys,
- X29 represents an amino acid residue selected from D-Ala and Gly,
- X31 represents Pro,
- R1 represents NH2,
- or a salt or solvate thereof.
- A still further embodiment relates to compounds of formula I, wherein
- X14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,
- X16 represents Lys,
- X29 represents D-Ala,
- X31 represents an amino acid residue selected from His and Pro,
- R1 represents NH2,
- or a salt or solvate thereof.
- Specific examples of compounds of formula I are the compounds of SEQ ID NO: 6-23, as well as salts or solvates thereof.
- Specific examples of compounds of formula I are the compounds of SEQ ID NO: 6, 9 and 11 as well as salts or solvates thereof.
- A specific example of compounds of formula I is the compound of SEQ ID NO: 6, well as salts or solvates thereof.
- A specific example of compounds of formula I is the compound of SEQ ID NO: 9, well as salts or solvates thereof.
- A specific example of peptidic compounds of formula I is the compound of SEQ ID NO: 11, well as salts or solvates thereof.
- In a further aspect, the present invention relates to a composition comprising a compound of the invention in admixture with a carrier. In preferred embodiments, the composition is a pharmaceutically acceptable composition and the carrier is a pharmaceutically acceptable carrier. The compound of the invention may be in the form of a salt, e.g. a pharmaceutically acceptable salt or a solvate, e.g. a hydrate. In still a further aspect, the present invention relates to a composition for use in a method of medical treatment, particularly in human medicine.
- The compounds of formula I are suitable for use in human treatment without an additional therapeutically effective agent. In other embodiments, however, the compounds may be used together with at least one additional therapeutically active agent, as described in "combination therapy".
- The compounds of formula I are particularly suitable for use in the treatment or prevention of diseases or disorders caused by, associated with and/or accompanied by disturbances in carbohydrate and/or lipid metabolism, e.g. for the treatment or prevention of hyperglycemia,
type 2 diabetes, impaired glucose tolerance,type 1 diabetes, obesity and metabolic syndrome. Further, the compounds of the invention may be suitable for use in the treatment or prevention of degenerative diseases, particularly neurodegenerative diseases. - The compounds described find use, inter alia, in preventing weight gain or promoting weight loss. By "preventing" is meant inhibiting or reducing when compared to the absence of treatment, and is not necessarily meant to imply complete cessation of a disorder.
- The compounds of the invention may cause a decrease in food intake and/or increase in energy expenditure, resulting in the observed effect on body weight.
- Independently of their effect on body weight, the compounds of the invention may have a beneficial effect on circulating cholesterol levels, being capable of improving lipid levels, particularly LDL, as well as HDL levels (e.g. increasing HDL/LDL ratio).
- Thus, the compounds of the invention may be used for direct or indirect therapy of any condition caused or characterised by excess body weight, such as the treatment and/or prevention of obesity, morbid obesity, obesity linked inflammation, obesity linked gallbladder disease, obesity induced sleep apnea. They may also be used for treatment and prevention of the metabolic syndrome, diabetes, hypertension, atherogenic dyslipidemia, atherosclerosis, arteriosclerosis, coronary heart disease, or stroke. Their effects in these conditions may be as a result of or associated with their effect on body weight, or may be independent thereof.
- Medical uses include delaying or preventing disease progression in
type 2 diabetes, treating metabolic syndrome, treating obesity or preventing overweight, for decreasing food intake, increase energy expenditure, reducing body weight, delaying the progression from impaired glucose tolerance (IGT) totype 2 diabetes; delaying the progression fromtype 2 diabetes to insulin-requiring diabetes; and hepatic steatosis. - The amino acid sequences of the present invention contain the conventional one letter and three letter codes for naturally occurring amino acids, as well as generally accepted three letter codes for other amino acids, such as Aib (a-aminoisobutyric acid).
- The term "native exendin-4" refers to native exendin-4 having the sequence HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2 (SEQ ID NO: 4).
- The invention relates to peptidic compounds as defined in formula I.
- The peptidic compounds of the present invention comprise a linear backbone of amino carboxylic acids linked by peptide, i.e. carboxamide bonds. Preferably, the amino carboxylic acids are α-amino carboxylic acids and more preferably L-α-amino carboxylic acids, unless indicated otherwise. The peptidic compounds preferably comprise a backbone sequence of 39 amino carboxylic acids.
- Amino acids within the peptide moiety (formula I) can be considered to be numbered consecutively from 1 to 39 in the conventional N-terminal to C-terminal direction. Reference to a "position" within peptidic moiety I should be constructed accordingly, as should reference to positions within native exendin-4 and other molecules, e.g., in exendin-4, His is at
position 1, Gly atposition 2, ..., Met atposition 14, ... and Ser at position 39. - An amino acid residue with an -NH2 side chain group, e.g. Lys, Orn, Dab or Dap, is functionalized in that at least one H atom of the -NH2 side chain group is replaced by -Z-C(O)-R5, wherein R5 comprises a lipophilic moiety, e.g. an acyclic linear or branched (C8-C30) saturated or unsaturated hydrocarbon group, which is unsubstituted or substituted e.g. by halogen (F, Cl, Br, J), -OH and/or CO2H and Z comprises a linker in all stereoisomeric forms, e.g. a linker comprising one or more, e.g. 1 to 5, preferably 1, 2 or 3 amino acid linker groups selected from the group gamma-Glutamate (gGlu), gAAA and AEEAc. Preferred groups R5 comprise a lipophilic moiety, e.g. an acyclic linear or branched (C12-C20) saturated or unsaturated hydrocarbon group, e.g. pentadecanyl, hexadecanyl or heptadecanyl, which is unsubstituted or substituted by CO2H, more preferably pentadecanyl, or heptadecanyl. In one embodiment amino acid linker groups are selected from gGlu, gGlu-gGlu, gGlu-gGlu-AEEAc, gGlu-AEEAc-gAAA, AEEAc-AEEAc-gGlu and AEEAc-AEEAc-AEEAc. In another embodiment the amino acid linker group is gGlu. In another embodiment the amino acid linker group is gGlu-gGlu. In another embodiment the amino acid linker group is gGlu-gGlu-AEEAc. In another embodiment the amino acid linker group is gGlu-AEEAc-gAAA. In another embodiment the amino acid linker group is AEEAc-AEEAc-gGlu. In another embodiment the amino acid linker group is AEEAc-AEEAc-AEEAc.
- In a further aspect, the present invention relates to a composition comprising a compound of the invention as described herein, or a salt or solvate thereof, in admixture with a carrier.
- The invention also relates to the use of a compound of the present invention for use as a medicament, particularly for the treatment of a condition as described in the specification.
- The invention also relates to a composition wherein the composition is a pharmaceutically acceptable composition, and the carrier is a pharmaceutically acceptable carrier.
- The skilled person is aware of a variety of different methods to prepare peptides. These methods include but are not limited to synthetic approaches and recombinant gene expression. Thus, one way of preparing these peptides is the synthesis in solution or on a solid support and subsequent isolation and purification. A different way of preparing the peptides is gene expression in a host cell in which a DNA sequence encoding the peptide has been introduced. Alternatively, the gene expression can be achieved without utilizing a cell system. The methods described above may also be combined in any way.
- A preferred way to prepare the compounds of the present invention is solid phase synthesis on a suitable resin. Solid phase peptide synthesis is a well-established methodology (see for example: Stewart and Young, Solid Phase Peptide Synthesis, Pierce Chemical Co., Rockford, III., 1984; E. Atherton and R. C. Sheppard, Solid Phase Peptide Synthesis. A Practical Approach, Oxford-IRL Press, New York, 1989). Solid phase synthesis is initiated by attaching an N-terminally protected amino acid with its carboxy terminus to an inert solid support carrying a cleavable linker. This solid support can be any polymer that allows coupling of the initial amino acid, e.g. a trityl resin, a chlorotrityl resin, a Wang resin or a Rink resin in which the linkage of the carboxy group (or carboxamide for Rink resin) to the resin is sensitive to acid (when Fmoc strategy is used). The polymer support must be stable under the conditions used to deprotect the α-amino group during the peptide synthesis.
- After the N-terminally protected first amino acid has been coupled to the solid support, the α-amino protecting group of this amino acid is removed. The remaining protected amino acids are then coupled one after the other or with a preformed dipeptide, tripeptide or tetrapeptide in the order represented by the peptide sequence using appropriate amide coupling reagents, for example BOP, HBTU, HATU or DIC (N,N'-diisopropylcarbodiimide) / HOBt (1-hydroxybenzotriazole), wherein BOP, HBTU and HATU are used with tertiary amine bases. Alternatively, the liberated N-terminus can be functionalized with groups other than amino acids, for example carboxylic acids, etc.
- Usually, reactive side-chain groups of the amino acids are protected with suitable blocking groups. These protecting groups are removed after the desired peptides have been assembled. They are removed concomitantly with the cleavage of the desired product from the resin under the same conditions. Protecting groups and the procedures to introduce protecting groups can be found in Protective Groups in Organic Synthesis, 3d ed., Greene, T. W. and Wuts, P. G. M., Wiley & Sons (New York: 1999).
- In some cases it might be desirable to have side-chain protecting groups that can selectively be removed while other side-chain protecting groups remain intact. In this case the liberated functionality can be selectively functionalized. For example, a lysine may be protected with an ivDde ([1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl) protecting group (S.R. Chhabra et al., Tetrahedron Lett. 39, (1998), 1603) which is labile to a very nucleophilic base, for example 4% hydrazine in DMF (dimethyl formamide). Thus, if the N-terminal amino group and all side-chain functionalities are protected with acid labile protecting groups, the ivDde group can be selectively removed using 4% hydrazine in DMF and the corresponding free amino group can then be further modified, e.g. by acylation. The lysine can alternatively be coupled to a protected amino acid and the amino group of this amino acid can then be deprotected resulting in another free amino group which can be acylated or attached to further amino acids. Alternatively, the side chain (as described in table 2) can be introduced together with the lysine during peptide synthesis using a prefunctionalized building block, e.g. (2S)-6-[[(4S)-5-tert-butoxy-4-[[(4S)-5-tert-butoxy-4-(hexadecanoylamino)-5-oxo-pentanoyl]amino]-5-oxo-pentanoyl]amino]-2-(9H-fluoren-9-ylmethoxycarbonylamino)hexanoic acid, as coupling partner.
- Finally the peptide is cleaved from the resin. This can be achieved by using King's cocktail (D. S. King, C. G. Fields, G. B. Fields, Int. J. Peptide Protein Res. 36, 1990, 255-266). The raw material can then be purified by chromatography, e.g. preparative RP-HPLC, if necessary.
- As used herein, the term "potency" or "in vitro potency" is a measure for the ability of a compound to activate the receptors for GLP-1, glucagon or GIP in a cell-based assay. Numerically, it is expressed as the "EC50 value", which is the effective concentration of a compound that induces a half maximal increase of response (e.g. formation of intracellular cAMP) in a dose-response experiment.
- Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing
type 2 diabetes, as well as atherosclerotic vascular disease, e.g. heart disease and stroke. Defining medical parameters for the metabolic syndrome include diabetes mellitus, impaired glucose tolerance, raised fasting glucose, insulin resistance, urinary albumin secretion, central obesity, hypertension, elevated triglycerides, elevated LDL cholesterol and reduced HDL cholesterol. - Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health and life expectancy and due to its increasing prevalence in adults and children it has become one of the leading preventable causes of death in modern world. It increases the likelihood of various other diseases, including heart disease,
type 2 diabetes, obstructive sleep apnoe, certain types of cancer, as well as osteoarthritis, and it is most commonly caused by a combination of excess food intake, reduced energy expenditure, as well as genetic susceptibility. - Diabetes mellitus, often simply called diabetes, is a group of metabolic diseases in which a person has high blood sugar levels, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced. The most common types of diabetes are: (1)
type 1 diabetes, where the body fails to produce insulin; (2)type 2 diabetes (T2DM), where the body fails to use insulin properly, combined with an increase in insulin deficiency over time, and (3) gestational diabetes, where women develop diabetes due to their pregnancy. All forms of diabetes increase the risk of long-term complications, which typically develop after many years. Most of these long-term complications are based on damage to blood vessels and can be divided into the two categories "macrovascular" disease, arising from atherosclerosis of larger blood vessels and "microvascular" disease, arising from damage of small blood vessels. Examples for macrovascular disease conditions are ischemic heart disease, myocardial infarction, stroke and peripheral vascular disease. Examples for microvascular diseases are diabetic retinopathy, diabetic nephropathy, as well as diabetic neuropathy. - The receptors for GLP-1 and GIP as well as glucagon are members of the family of 7-transmembrane-spanning, heterotrimeric G-protein coupled receptors. They are structurally related to each other and share not only a significant level of sequence identity, but have also similar mechanisms of ligand recognition and intracellular signaling pathways.
- Similarly, the peptides GLP-1, GIP and glucagon share regions of high sequence identity/similarity. GLP-1 and glucagon are produced from a common precursor, preproglucagon, which is differentially processed in a tissue-specific manner to yield e.g. GLP-1 in intestinal endocrine cells and glucagon in alpha cells of pancreatic islets. GIP is derived from a larger proGIP prohormone precursor and is synthesized and released from K-cells located in the small intestine.
- The peptidic incretin hormones GLP-1 and GIP are secreted by intestinal endocrine cells in response to food and account for up to 70% of meal-stimulated insulin secretion. Evidence suggests that GLP-1 secretion is reduced in subjects with impaired glucose tolerance or
type 2 diabetes, whereas responsiveness to GLP-1 is still preserved in these patients. Thus, targeting of the GLP-1 receptor with suitable agonists offers an attractive approach for treatment of metabolic disorders, including diabetes. The receptor for GLP-1 is distributed widely, being found mainly in pancreatic islets, brain, heart, kidney and the gastrointestinal tract. In the pancreas, GLP-1 acts in a strictly glucose-dependent manner by increasing secretion of insulin from beta cells. This glucose-dependency shows that activation of GLP-1 receptors is unlikely to cause hypoglycemia. Also the receptor for GIP is broadly expressed in peripheral tissues including pancreatic islets, adipose tissue, stomach, small intestine, heart, bone, lung, kidney, testis, adrenal cortex, pituitary, endothelial cells, trachea, spleen, thymus, thyroid and brain. Consistent with its biological function as incretin hormone, the pancreatic β-cell express the highest levels of the receptor for GIP in humans. - There is some clinical evidence that the GIP-receptor mediated signaling could be impaired in patients with T2DM but the impairment of GIP-action is shown to be reversible and could be restored with improvement of the diabetic status. Of note, the stimulation of insulin secretion by both incretin hormones, GIP and GLP-1, is strictly glucose-dependent ensuring a fail-safe mechanism associated with a low risk for hypoglycemia.
- At the beta cell level, GLP-1 and GIP have been shown to promote glucose sensitivity, neogenesis, proliferation, transcription of proinsulin and hypertrophy, as well as anti-apoptosis. A peptide with both agonistic activity for the GLP-1 and the GIP receptor could be anticipated to have additive or synergistic anti-diabetic benefit. Other relevant effects of GLP-1 beyond the pancreas include delayed gastric emptying, increased satiety, decreased food intake, reduction of body weight, as well as neuroprotective and cardioprotective effects. In patients with
type 2 diabetes, such extrapancreatic effects could be particularly important considering the high rates of comorbidities like obesity and cardiovascular disease. Further GIP actions in peripheral tissues beyond the pancreas comprise increased bone formation and decreased bone resorption as well as neuroprotective effects which might be beneficial for the treatment of osteoporosis and cognitive defects like Alzheimer's disease. - Glucagon is a 29 amino acid peptide hormone that is produced by pancreatic alpha cells and released into the bloodstream when circulating glucose is low. An important physiological role of glucagon is to stimulate glucose output in the liver, which is a process providing the major counterregulatory mechanism for insulin in maintaining glucose homeostasis in vivo.
- Glucagon receptors are however also expressed in extra-hepatic tissues such as kidney, heart, adipocytes, lymphoblasts, brain, retina, adrenal gland and gastrointestinal tract, suggesting a broader physiological role beyond glucose homeostasis. Accordingly, recent studies have reported that glucagon has therapeutically positive effects on energy management, including stimulation of energy expenditure and thermogenesis, accompanied by reduction of food intake and body weight loss. Altogether, stimulation of glucagon receptors might be useful in the treatment of obesity and the metabolic syndrome.
- Oxyntomodulin is a peptide hormone consisting of glucagon with an eight amino acids encompassing C-terminal extension. Like GLP-1 and glucagon, it is pre-formed in preproglucagon and cleaved and secreted in a tissue-specific manner by endocrinal cells of the small bowel. Oxyntomodulin is known to stimulate both, the receptors for GLP-1 and glucagon and is therefore the prototype of a dual agonist (see Pocai, Molecular Metabolism 2013; 3:241-51).
- As GLP-1 and GIP are known for their anti-diabetic effects, GLP-1 and glucagon are both known for their food intake-suppressing effects and glucagon is also a mediator of additional energy expenditure, it is conceivable that a combination of the activities of the three hormones in one molecule can yield a powerful medication for treatment of the metabolic syndrome and in particular its components diabetes and obesity.
- Accordingly, the compounds of the invention may be used for treatment of glucose intolerance, insulin resistance, pre-diabetes, increased fasting glucose (hyperglycemia),
type 2 diabetes, hypertension, dyslipidemia, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke or any combination of these individual disease components. - In addition, they may be used for control of appetite, feeding and calory intake, increase of energy expenditure, prevention of weight gain, promotion of weight loss, reduction of excess body weight and altogether treatment of obesity, including morbid obesity.
- The compounds of the invention are agonists for the receptors for GLP-1, GIP and for glucagon (e.g. "trigonal agonists") and may provide therapeutic benefit to address a clinical need for targeting the metabolic syndrome by allowing simultaneous treatment of diabetes and obesity.
- Further disease states and health conditions which could be treated with the compounds of the invention are obesity-linked inflammation, obesity-linked gallbladder disease and obesity-induced sleep apnea.
- Although all these conditions could be associated directly or indirectly with obesity, the effects of the compounds of the invention may be mediated in whole or in part via an effect on body weight, or independent thereof.
- Further, diseases to be treated may be neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease, or other degenerative diseases as described above.
- In one embodiment the compounds are useful in the treatment or prevention of hyperglycemia,
type 2 diabetes and/or obesity. - The compounds of the invention may have the ability to reduce the intestinal passage, increase the gastric content and/or to reduce the food intake of a patient. These activities of the compounds of the invention can be assessed in animal models known to the skilled person and also described herein in the Methods.
- The compounds of the invention have the ability to reduce blood glucose level, and/or to reduce HbA1c levels of a patient. These activities of the compounds of the invention can be assessed in animal models known to the skilled person and also described herein in the Methods and in examples.
- The compounds of the invention may have the ability to reduce body weight of a patient. These activities of the compounds of the invention can be assessed in animal models known to the skilled person and also described herein in the Methods and in examples.
- The compounds of the invention may be useful in the treatment or prevention of hepatosteatosis, preferably non-alcoholic liver-disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
- The term "pharmaceutical composition" indicates a mixture containing ingredients that are compatible when mixed and which may be administered. A pharmaceutical composition may include one or more medicinal drugs. Additionally, the pharmaceutical composition may include carriers, buffers, acidifying agents, alkalizing agents, solvents, adjuvants, tonicity adjusters, emollients, expanders, preservatives, physical and chemical stabilizers e.g. surfactants, antioxidants and other components, whether these are considered active or inactive ingredients. Guidance for the skilled in preparing pharmaceutical compositions may be found, for example, in Remington: The Science and Practice of Pharmacy, (20th ed.) ed. A. R. Gennaro, 2000, Lippencott Williams & Wilkins and in R.C.Rowe et al (Ed), Handbook of Pharmaceutical Excipients, PhP, May 2013 update.
- The exendin-4 peptide derivatives of the present invention, or salts thereof, are administered in conjunction with an acceptable pharmaceutical carrier, diluent, or excipient as part of a pharmaceutical composition.
- A "pharmaceutically acceptable carrier" is a carrier which is physiologically acceptable (e.g. physiologically acceptable pH) while retaining the therapeutic properties of the substance with which it is administered. Standard acceptable pharmaceutical carriers and their formulations are known to one skilled in the art and described, for example, in Remington: The Science and Practice of Pharmacy, (20th ed.) ed. A. R. Gennaro , 2000, Lippencott Williams & Wilkins and in R.C.Rowe et al (Ed), Handbook of Pharmaceutical excipients, PhP, May 2013 update. One exemplary pharmaceutically acceptable carrier is physiological saline solution.
- In one embodiment carriers are selected from the group of buffers (e.g. citrate/citric acid, acetate/acetic acid), acidifying agents (e.g. hydrochloric acid), alkalizing agents (e.g. sodium hydroxide), preservatives (e.g. phenol, m-cresol), co-solvents (e.g. polyethylene glycol 400), tonicity adjusters (e.g. mannitol, glycerol), stabilizers (e.g. surfactant, antioxidants, amino acids).
- Concentrations used are in a range that is physiologically acceptable.
- Acceptable pharmaceutical carriers or diluents include those used in formulations suitable for oral, rectal, nasal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and transdermal) administration. The compounds of the present invention will typically be administered parenterally.
- The term "pharmaceutically acceptable salt" means salts of the compounds of the invention which are safe and effective for use in mammals.
- The term "solvate" means complexes of the compounds of the invention or salts thereof with solvent molecules, e.g. organic solvent molecules and/or water.
- In the pharmaceutical composition, the exendin-4 derivative can be in monomeric or oligomeric form.
- The term "therapeutically effective amount" of a compound refers to a nontoxic but sufficient amount of the compound to provide the desired effect. The amount of a compound of the formula I necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. An appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. For example the "therapeutically effective amount" of a compound of the formula I is about 0.01 to 50 mg/dose, preferably 0.02 to 1 mg/dose.
- Pharmaceutical compositions of the invention are those suitable for parenteral (for example subcutaneous, intramuscular, intradermal or intravenous), rectal, topical and peroral (for example sublingual) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula I used in each case. In one embodiment, application is parenteral, e.g. subcutaneous.
- In case of parenteral application, it could be favorable for the corresponding formulations to include at least one antimicrobial preservative in order to inhibit the growth of microbes and bacteria between administrations. Preferred preservatives are benzylic alcohol or phenolic compounds like phenol or m-cresol. It has been described that these ingredients can induce aggregation for peptides and proteins leading to lower solubility and stability in the formulation (see R. L. Bis et al., Int. J. Pharm. 472, 356-361, 2014; T. J. Kamerzell, Adv. Drug Deliv. Rev., 63, 1118-1159, 2011).
- Suitable pharmaceutical compositions may be in the form of separate units, for example capsules, tablets and powders in vials or ampoules, each of which contains a defined amount of the compound; as powders or granules; as solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. It may be provided in single or multiple dose injectable form, for example in the form of a pen. The compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact.
- In certain embodiments the pharmaceutical composition may be provided together with a device for application, for example together with a syringe, an injection pen or an autoinjector. Such devices may be provided separate from a pharmaceutical composition or prefilled with the pharmaceutical composition.
- The compound(s) of the present invention can be prepared for use in suitable pharmaceutical compositions. The suitable pharmaceutical compositions may be in the form of one or more administration units.
- The compositions may be prepared by any suitable pharmaceutical method which includes a step in which the compound(s) of the present invention and the carrier (which may consist of one or more additional ingredients) are brought into contact. The administration units may be for example capsules, tablets, dragées, granules sachets, drops, solutions, suspensions, lyophylisates and powders, each of which contains a defined amount of the compound(s) of the present invention.
- Each of the above-mentioned administration units of the compound(s) of the invention or pharmaceutical composition of the invention (administration units) may be provided in a package for easy transport and storage. The administration units are packaged in standard single or multi-dosage packaging, their form, material and shape depending on the type of units prepared.
- For example, tablets and other forms of solid administration units can be packaged in single units, and the single packaged units can be packaged in multi-pack containers. Liquid formulations can be packaged in single units, such as e.g. vials, cartridges, syringes/prefilled syringes, infusion bags, collapsible plastic bags, infusion bottles, blow-filled seal bottles or infusion tubings or in single or multiple dose injectable form, for example in the form of a pen device, pump or syringe and the single packaged units can be packaged in multi-pack containers. A single package may comprise only one or a plurality of administration units. The package may for example be made of paper, cardboard, paperboard, plastic, metal, combinations or laminates of one or more of paper, plastics and metal, or glass. Exemplary embodiments are blister packages containing e.g. tablets or capsules, which in turn may be provided inside a cardboard box, aluminum barrier laminate sachets containing e.g. a powder, glass or plastic bottles containing e.g. tablets or a solution, or vials, cartridges, syringes, infusion bags, infusion bottles, infusion tubings or ampoules containing a solution or suspension.
- In certain embodiments administration units may be provided together with a device for application, for example together with a syringe, an injection pen or an autoinjector. Such devices may be provided separate from a pharmaceutical composition or prefilled with the pharmaceutical composition.
- A "pen-type injection device", often briefly referred to as "injection pen", is typically an injection device having an elongated shape that resembles to a fountain pen for writing. Although such pens usually have a tubular cross-section, they could easily have a different cross-section such as triangular, rectangular or square or any variation around these geometries. Generally, pen-type injection devices comprise three primary elements: a cartridge section that includes a cartridge often contained within a housing or holder; a needle assembly connected to one end of the cartridge section; and a dosing section connected to the other end of the cartridge section. The cartridge, often also referred to as "ampoule", typically includes a reservoir that is filled with a medication, a movable rubber type bung or stopper located at one end of the cartridge reservoir, and a top having a pierceable rubber seal located at the other, often necked-down, end. A crimped annular metal band is typically used to hold the rubber seal in place. While the cartridge housing may be typically made of plastic, cartridge reservoirs have historically been made of glass.
- The compounds of the present invention, trigonal agonists for the GLP-1, GIP and glucagon receptors, can be widely combined with other pharmacologically active compounds, such as all drugs mentioned in the Rote Liste 2016, e.g. with all weight-reducing agents or appetite suppressants mentioned in the Rote Liste 2016,
chapter 1, all lipid-lowering agents mentioned in the Rote Liste 2016, chapter 58, all antihypertensives and nephroprotectives, mentioned in the Rote Liste 2016, or all diuretics mentioned in the Rote Liste 2015, chapter 36. - The active ingredient combinations can be used especially for a synergistic improvement in action. They can be applied either by separate administration of the active ingredients to the patient or in the form of combination products in which a plurality of active ingredients are present in one pharmaceutical preparation. When the active ingredients are administered by separate administration of the active ingredients, this can be done simultaneously or successively.
- Other active substances which are suitable for such combinations include in particular those which for example potentiate the therapeutic effect of one or more active substances with respect to one of the indications mentioned and/or which allow the dosage of one or more active substances to be reduced.
- Therapeutic agents which are suitable for combinations include, for example, antidiabetic agents such as:
Insulin and Insulin derivatives, for example: Glargine / Lantus®, 270 - 330U/mL of insulin glargine (EP 2387989 A ), 300U/mL of insulin glargine (EP 2387989 A ), Glulisin /Apidra®, Detemir / Levemir®, Lispro / Humalog® / Liprolog®, Degludec / DegludecPlus, Aspart, basal insulin and analogues (e.g.LY-2605541, LY2963016, NN1436), PEGylated insulin Lispro, Humulin®, Linjeta, SuliXen®, NN1045, Insulin plus Symlin, PE0139, fast-acting and short-acting insulins (e.g. Linjeta, PH20, NN1218, HinsBet), (APC-002)hydrogel, oral, inhalable, transdermal and sublingual insulins (e.g. Exubera®, Nasulin®, Afrezza, Tregopil, TPM 02, Capsulin, Oral-lyn®, Cobalamin® oral insulin, ORMD-0801, NN1953, NN1954, NN1956, VIAtab, Oshadi oral insulin). Additionally included are also those insulin derivatives which are bonded to albumin or another protein by a bifunctional linker. - GLP-1, GLP-1 analogues and GLP-1 receptor agonists, for example: Lixisenatide / AVE0010 / ZP10 / Lyxumia, Exenatide / Exendin-4 / Byetta / Bydureon / ITCA 650 / AC-2993, Liraglutide / Victoza, Semaglutide, Taspoglutide, Syncria / Albiglutide, Dulaglutide, rExendin-4, CJC-1134-PC, PB-1023, TTP-054, Efpeglenatide / HM-11260C, CM-3, GLP-1 Eligen, ORMD-0901, NN-9924, NN-9926, NN-9927, Nodexen, Viador-GLP-1, CVX-096, ZYOG-1, ZYD-1, GSK-2374697, DA-3091, MAR-701, MAR709, ZP-2929, ZP-3022, ZP-DI-70, TT-401, MK-8521, MEDI0382, BHM-034,HM12525A, MOD-6030, CAM-2036, DA-15864, ARI-2651, ARI-2255, LY3298176, NN1177, Exenatide-XTEN and Glucagon- XTEN, NN9030.
- DPP-4 inhibitors, for example: Alogliptin / Nesina, Trajenta / Linagliptin / BI-1356 / Ondero / Trajenta / Tradjenta / Trayenta / Tradzenta, Saxagliptin / Onglyza, Sitagliptin / Januvia / Xelevia / Tesave / Janumet / Velmetia, Galvus / Vildagliptin, Anagliptin, Gemigliptin, Teneligliptin, Melogliptin, Trelagliptin, DA-1229, Omarigliptin / MK-3102, KM-223, Evogliptin, ARI-2243, PBL-1427, Pinoxacin.
- SGLT2 inhibitors, for example: Invokana / Canaglifozin, Forxiga / Dapagliflozin, Remoglifozin, Sergliflozin, Empagliflozin, Ipragliflozin, Tofogliflozin, Luseogliflozin, Sotagliflozin (LX-4211), Ertuglifozin / PF-04971729, RO-4998452, Bexagliflozin (EGT-0001442), KGA-3235 / DSP-3235, LIK066, SBM-TFC-039, Henagliflozin (SHR3824), Janagliflozin, Tianagliflozin, AST1935, JRP493, HEC-44616 Biguanides (e.g. Metformin, Buformin, Phenformin), Thiazolidinediones (e.g. Pioglitazone, Rivoglitazone, Rosiglitazone, Troglitazone), dual PPAR agonists (e.g. Aleglitazar, Muraglitazar, Tesaglitazar), Sulfonylureas (e.g. Tolbutamide, Glibenclamide, Glimepiride/Amaryl, Glipizide), Meglitinides (e.g. Nateglinide, Repaglinide, Mitiglinide), Alpha-glucosidase inhibitors (e.g. Acarbose, Miglitol, Voglibose), Amylin and Amylin analogues (e.g. Pramlintide, Symlin).
- GPR119 agonists (e.g. GSK-263A, PSN-821, MBX-2982, APD-597, ZYG-19, DS-8500), GPR40 agonists (e.g. Fasiglifam / TAK-875, TUG-424, P-1736, JTT-851, GW9508).
- Other suitable combination partners are: Cycloset, inhibitors of 11-beta-HSD (e.g. LY2523199, BMS770767, RG-4929, BMS816336, AZD-8329, HSD-016, BI-135585), activators of glucokinase (e.g. TTP-399, AMG-151, TAK-329, GKM-001), inhibitors of DGAT (e.g. LCQ-908), inhibitors of protein tyrosinephosphatase 1 (e.g. Trodusquemine), inhibitors of glucose-6-phosphatase, inhibitors of fructose-1,6-bisphosphatase, inhibitors of glycogen phosphorylase, inhibitors of phosphoenol pyruvate carboxykinase, inhibitors of glycogen synthase kinase, inhibitors of pyruvate dehydrokinase, alpha2-antagonists, CCR-2 antagonists, SGLT-1 inhibitors (e.g. LX-2761).
- One or more lipid lowering agents are also suitable as combination partners, such as for example: HMG-CoA-reductase inhibitors (e.g. Simvastatin, Atorvastatin), fibrates (e.g. Bezafibrate, Fenofibrate), nicotinic acid and the derivatives thereof (e.g. Niacin), PPAR-(alpha, gamma or alpha/gamma) agonists or modulators (e.g. Aleglitazar), PPAR-delta agonists, ACAT inhibitors (e.g. Avasimibe), cholesterol absorption inhibitors (e.g. Ezetimibe), Bile acid-binding substances (e.g. Cholestyramine), ileal bile acid transport inhibitors, MTP inhibitors, or modulators of PCSK9.
- HDL-raising compounds such as: CETP inhibitors (e.g. Torcetrapib, Anacetrapid, Dalcetrapid, Evacetrapid, JTT-302, DRL-17822, TA-8995) or ABC1 regulators.
- Other suitable combination partners are one or more active substances for the treatment of obesity, such as for example: Sibutramine, Tesofensine, Orlistat, antagonists of the cannabinoid-1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists (e.g. Velneperit), beta-3-agonists, leptin or leptin mimetics, agonists of the 5HT2c receptor (e.g. Lorcaserin), or the combinations of bupropione/naltrexone, bupropione/zonisamide, bupropione/phentermine or pramlintide/metreleptin.
- Other suitable combination partners are:
- Further gastrointestinal peptides such as Peptide YY 3-36 (PYY3-36) or analogues thereof, pancreatic polypeptide (PP) or analogues thereof.
- Glucagon receptor agonists or antagonists, GIP receptor agonists or antagonists, ghrelin antagonists or inverse agonists, Xenin and analogues thereof.
- Moreover, combinations with drugs for influencing high blood pressure, chronic heart failure or atherosclerosis, such as e.g.: Angiotensin II receptor antagonists (e.g. telmisartan, candesartan, valsartan, losartan, eprosartan, irbesartan, olmesartan, tasosartan, azilsartan), ACE inhibitors, ECE inhibitors, diuretics, beta-blockers, calcium antagonists, centrally acting hypertensives, antagonists of the alpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors and others or combinations thereof are suitable.
- In another aspect, this invention relates to the use of a compound according to the invention or a physiologically acceptable salt thereof combined with at least one of the active substances described above as a combination partner, for preparing a medicament which is suitable for the treatment or prevention of diseases or conditions which can be affected by binding to the receptors for GLP-1 and glucagon and by modulating their activity. This is preferably a disease in the context of the metabolic syndrome, particularly one of the diseases or conditions listed above, most particularly diabetes or obesity or complications thereof.
- The use of the compounds according to the invention, or a physiologically acceptable salt thereof, in combination with one or more active substances may take place simultaneously, separately or sequentially.
- The use of the compound according to the invention, or a physiologically acceptable salt thereof, in combination with another active substance may take place simultaneously or at staggered times, but particularly within a short space of time. If they are administered simultaneously, the two active substances are given to the patient together; if they are used at staggered times, the two active substances are given to the patient within a period of less than or equal to 12 hours, but particularly less than or equal to 6 hours.
- Consequently, in another aspect, this invention relates to a medicament which comprises a compound according to the invention or a physiologically acceptable salt of such a compound and at least one of the active substances described above as combination partners, optionally together with one or more inert carriers and/or diluents.
- The compound according to the invention, or physiologically acceptable salt or solvate thereof, and the additional active substance to be combined therewith may both be present together in one formulation, for example a tablet or capsule, or separately in two identical or different formulations, for example as so-called kit-of-parts.
-
-
Figure 1 . Comparison of Dynamic Debye plots for peptide formulations exhibiting reversible self-association (attractive interactions) and repulsive virial interactions -
Figure 2 . SEQ ID NO: 6, SEQ ID NO: 7 - Blood glucose profile following first treatment in fed DIO mice -
Figure 3 . SEQ ID NO: 6, SEQ ID NO: 7 - Body mass in DIO mice -
Figure 4 . SEQ ID NO: 6, SEQ ID NO: 7 - Body mass change in DIO mice -
Figure 5 . SEQ ID SEQ ID NO: 6, SEQ ID NO: 7 - Whole body fat mass change in DIO mice (n=8/group, n=7 DIO-Vehicle) -
Figure 6 . SEQ ID NO: 6, SEQ ID NO: 7 - Terminal liver mass in DIO mice -
Figure 7 . SEQ ID NO: 6, SEQ ID NO: 7 - Terminal plasma alanine aminotransferase (ALAT) concentrations in DIO mice (n=8/group, n=7 DIO-Vehicle) -
Figure 8 . SEQ ID NO: 6, SEQ ID NO: 7 - Terminal total plasma cholesterol concentrations in DIO mice -
Figure 9 . SEQ ID NO: 6, SEQ ID NO: 7 - Terminal plasma insulin concentrations in DIO mice -
Figure 10 . SEQ ID NO: 6, SEQ ID NO: 7 - Blood glucose profile following single treatment in fed db/db mice -
Figure 11 . SEQ ID NO: 6, SEQ ID NO: 7 - Blood glucose area under the curve (AUC) in fed db/db mice -
Figure 12 . SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 - Blood glucose profile following first treatment in fed DIO mice -
Figure 13 . SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10 - Body mass in DIO mice -
Figure 14 . SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10 - Body mass change in DIO mice -
Figure 15 . SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10 - Whole body fat mass change in DIO mice -
Figure 16 . SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10 - Terminal liver mass in DIO mice -
Figure 17 . SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10 - Terminal plasma alanine aminotransferase concentrations in DIO mice -
Figure 18 . SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10 - Terminal total plasma cholesterol concentrations in DIO mice -
Figure 19 . SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10 - Terminal plasma insulin concentrations in DIO mice -
Figure 20 . SEQ ID NO: 13 - Blood glucose profile following single treatment in fed db/db mice -
Figure 21 . SEQ ID NO: 13 - Blood glucose area under the curve (AUC) in fed db/db mice -
- AA
- amino acid
- AEEAc
- (2-(2-aminoethoxy)ethoxy)acetyl
- Aib
- alpha-amino-isobutyric acid
- cAMP
- cyclic adenosine monophosphate
- Boc
- tert-butyloxycarbonyl
- BOP
- (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate
- BSA
- bovine serum albumin
- tBu
- tertiary butyl
- dAla
- D-alanine
- DCM
- dichloromethane
- Dde
- 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-ethyl
- ivDde
- 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methyl-butyl
- DIC
- N,N'-diisopropylcarbodiimide
- DIPEA
- N,N-diisopropylethylamine
- DMEM
- Dulbecco's modified Eagle's medium
- DMF
- dimethyl formamide
- DMS
- dimethylsulfide
- EDT
- ethanedithiol
- FA
- formic acid
- FBS
- fetal bovine serum
- Fmoc
- fluorenylmethyloxycarbonyl
- gAAA
- gamma-amino adipic acid
- gGlu
- gamma-glutamate (γE)
- HATU
- O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
- HBSS
- Hanks' Balanced Salt Solution
- HBTU
- 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate
- HEPES
- 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid
- HOBt
- 1-hydroxybenzotriazole
- HOSu
- N-hydroxysuccinimide
- HPLC
- High Performance Liquid Chromatography
- HTRF
- Homogenous Time Resolved Fluorescence
- IBMX
- 3-isobutyl-1-methylxanthine
- LC/MS
- Liquid Chromatography/Mass Spectrometry
- Mmt
- monomethoxy-trityl
- Palm
- palmitoyl
- PBS
- phosphate buffered saline
- PEG
- polyethylene glycole
- PK
- pharmacokinetic
- RP-HPLC
- reversed-phase high performance liquid chromatography
- Stea
- stearyl
- TFA
- trifluoroacetic acid
- Trt
- trityl
- UV
- ultraviolet
- Different Rink-Amide resins (4-(2',4'-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucylaminomethyl resin, Merck Biosciences; 4-[(2,4-Dimethoxyphenyl)(Fmoc-amino)methyl]phenoxy acetamido methyl resin, Agilent Technologies) were used for the synthesis of peptide amides with loadings in the range of 0.2-0.7 mmol/g.
- Fmoc protected natural amino acids were purchased from Protein Technologies Inc., Senn Chemicals, Merck Biosciences, Novabiochem, Iris Biotech, Bachem, Chem-Impex International or MATRIX Innovation. The following standard amino acids were used throughout the syntheses: Fmoc-L-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-L-Asn(Trt)-OH, Fmoc-L-Asp(OtBu)-OH, Fmoc-L-Cys(Trt)-OH, Fmoc-L-Gln(Trt)-OH, Fmoc-L-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-L-His(Trt)-OH, Fmoc-L-Ile-OH, Fmoc-L-Leu-OH, Fmoc-L-Lys(Boc)-OH, Fmoc-L-Met-OH, Fmoc-L-Phe-OH, Fmoc-L-Pro-OH, Fmoc-L-Ser(tBu)-OH, Fmoc-L-Thr(tBu)-OH, Fmoc-L-Trp(Boc)-OH, Fmoc-L-Tyr(tBu)-OH, Fmoc-L-Val-OH.
- In addition, the following special amino acids were purchased from the same suppliers as above: Fmoc-L-Lys(ivDde)-OH, Fmoc-L-Lys(Mmt)-OH, Fmoc-Aib-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-D-Ala-OH, Boc-L-His(Boc)-OH (available as toluene solvate) and Boc-L-His(Trt)-OH.
- Furthermore, the building blocks (2S)-6-[[(4S)-5-tert-butoxy-4-[[(4S)-5-tert-butoxy-4-(hexadecanoylamino)-5-oxo-pentanoyl]amino]-5-oxo-pentanoyl]amino]-2-(9H-fluoren-9-ylmethoxycarbonylamino)hexanoic acid and Boc-L-His(Trt)-Aib-OH can be applied. Both building blocks are synthesized separately.
- The solid phase peptide syntheses were performed for example on a Prelude Peptide Synthesizer (Protein Technologies Inc) or similar automated synthesizer using standard Fmoc chemistry and HBTU/DIPEA activation. DMF was used as the solvent. Deprotection : 20% piperidine/DMF for 2 × 2.5 min. Washes: 7 × DMF. Coupling 2:5:10 200 mM AA/ 500 mM HBTU / 2M DIPEA in
DMF 2 × for 20 min. - Washes: 5 × DMF.
- In cases where a Lys-side-chain was modified, Fmoc-L-Lys(ivDde)-OH or Fmoc-L-Lys(Mmt)-OH was used in the corresponding position. After completion of the synthesis, the ivDde group was removed according to a modified literature procedure (S.R. Chhabra et al., Tetrahedron Lett., 1998, 39, 1603), using 4% hydrazine hydrate in DMF. The Mmt group was removed by repeated treatment with AcOH/TFE/DCM (1/2/7) for 15 minutes at RT, the resin then repeatedly washed with DCM, 5% DIPEA in DCM and 5% DIPEA in DCM/DMF.
- The following acylations were carried out by treating the resin with the N-hydroxy succinimide esters of the desired acid or using coupling reagents like HBTU/DIPEA or HOBt/DIC.
- All the peptides that have been synthesized were cleaved from the resin with King's cleavage cocktail consisting of 82.5% TFA, 5% phenol, 5% water, 5% thioanisole, 2.5% EDT. The crude peptides were then precipitated in diethyl or diisopropyl ether, centrifuged, and lyophilized. Peptides were analyzed by analytical HPLC and checked by ESI mass spectrometry. Crude peptides were purified by a conventional preparative RP-HPLC purification procedure.
- Alternatively, peptides were synthesized by a manual synthesis procedure:
0.3 g Desiccated Rink amide MBHA Resin (0.66 mmol/g) was placed in a polyethylene vessel equipped with a polypropylene filter. Resin was swollen in DCM (15 ml) for 1 h and DMF (15 ml) for 1h. The Fmoc group on the resin was de-protected by treating it twice with 20% (v/v) piperidine/DMF solution for 5 and 15 min. The resin was washed with DMF/DCM/DMF (6:6:6 time each). A Kaiser test (quantitative method) was used for the conformation of removal of Fmoc from solid support. The C-terminal Fmoc-amino acid (5 equiv. excess corresponding to resin loading) in dry DMF was added to the de-protected resin and coupling of the next Fmoc-amino acid was initiated with 5 equivalent excess of DIC and HOBT in DMF. The concentration of each reactant in the reaction mixture was approximately 0.4 M. The mixture was rotated on a rotor at room temperature for 2 h. Resin was filtered and washed with DMF/DCM/DMF (6:6:6 time each). Kaiser test on peptide resin aliquot upon completion of coupling was negative (no colour on the resin). After the first amino acid attachment, the unreacted amino group, if any, in the resin was capped used acetic anhydride/pyridine/DCM (1:8:8) for 20 minutes to avoid any deletion of the sequence. After capping, resin was washed with DCM/DMF/DCM/DMF (6/6/6/6 time each). The Fmoc group on the C-terminal amino acid attached peptidyl resin was deprotected by treating it twice with 20% (v/v) piperidine/DMF solution for 5 and 15 min. The resin was washed with DMF/DCM/DMF (6:6:6 time each). The Kaiser test on peptide resin aliquot upon completion of Fmoc-deprotection was positive. - The remaining amino acids in target sequence on Rink amide MBHA Resin were sequentially coupled using Fmoc AA/DIC/HOBt method using 5 equivalent excess corresponding to resin loading in DMF. The concentration of each reactant in the reaction mixture was approximately 0.4 M. The mixture was rotated on a rotor at room temperature for 2 h. Resin was filtered and washed with DMF/DCM/DMF (6:6:6 time each). After each coupling step and Fmoc deprotection step, a Kaiser test was carried out to confirm the completeness of the reaction.
- After the completion of the linear sequence, the ε-amino group of lysine used as branching point or modification point was deprotected by using 2.5% hydrazine hydrate in DMF for 15 min × 2 and washed with DMF/DCM/DMF (6:6:6 time each). The γ-carboxyl end of glutamic acid was attached to the ε-amino group of Lys using Fmoc-Glu(OH)-OtBu with DIC/HOBt method (5 equivalent excess with respect to resin loading) in DMF. The mixture was rotated on a rotor at room temperature for 2 h. The resin was filtered and washed with DMF/DCM/DMF (6x30 ml each). The Fmoc group on the glutamic acid was de-protected by treating it twice with 20% (v/v) piperidine/DMF solution for 5 and 15 min (25 ml each). The resin was washed with DMF/ DCM/DMF (6:6:6 time each). A Kaiser test on peptide resin aliquot upon completion of Fmoc-deprotection was positive.
- If the side-chain branching also contains one more γ-glutamic acid, a second Fmoc-Glu(OH)-OtBu used for the attachment to the free amino group of γ-glutamic acid with DIC/HOBt method (5 equivalent excess with respect to resin loading) in DMF. The mixture was rotated on a rotor at room temperature for 2 h. Resin was filtered and washed with DMF/ DCM/DMF (6x30 ml each). The Fmoc group on the γ-glutamic acid was de-protected by treating it twice with 20% (v/v) piperidine/DMF solution for 5 and 15 min (25 mL). The resin was washed with DMF/ DCM/DMF (6:6:6 time each). A Kaiser test on peptide resin aliquot upon completion of Fmoc-deprotection was positive.
- Palmitic acid and stearic acid attachment to side chains of glutamic acid:
To the free amino group of γ-glutamic acid, palmitic acid or stearic acid (5 equiv.) dissolved in DMF was added and coupling was initiated by the addition of DIC (5 equiv.) and HOBt (5 equiv.) in DMF. The resin was washed with DMF/DCM/DMF (6:6:6 time each). - Final cleavage of peptide from the resin:
- The peptidyl resin synthesized by manual synthesis was washed with DCM (6x10 ml), MeOH (6x10 ml) and ether (6x10 ml) and dried in vacuum desiccators overnight.
- The cleavage of the peptide from the solid support was achieved by treating the peptide-resin with reagent cocktail (80.0% TFA/ 5% thioanisole/5% phenol/ 2.5 % EDT, 2.5 % DMS and 5 % DCM) at room temperature for 3 h. Cleavage mixture was collected by filtration and the resin was washed with TFA (2 ml) and DCM (2 × 5 ml).
- The excess TFA and DCM was concentrated to small volume under nitrogen and a small amount of DCM (5-10 ml) was added to the residue and evaporated under nitrogen. The process was repeated 3-4 times to remove most of the volatile impurities. The residue was cooled to 0°C and anhydrous ether was added to precipitate the peptide. The precipitated peptide was centrifuged and the supernatant ether was removed and fresh ether was added to the peptide and re-centrifuged. The crude sample was preparative HPLC purified and lyophilized. The identity of peptide was confirmed by LCMS.
- In addition, a different route for the introduction of the lysine side chain is used, applying a prefunctionalized building block where the side chain is already attached to the lysine (e.g. (2S)-6-[[(4S)-5-tert-butoxy-4-[[(4S)-5-tert-butoxy-4-(hexadecanoylamino)-5-oxo-pentanoyl]amino]-5-oxo-pentanoyl]amino]-2-(9H-fluoren-9-ylmethoxycarbonylamino)hexanoic acid) as coupling partner in the peptide synthesis. 0,67mmol of peptide resin bearing an amino-group is washed with 20ml of dimethylformamide. 2,93g of (2S)-6-[[(4S)-5-tert-butoxy-4-[[(4S)-5-tert-butoxy-4-(hexadecanoylamino)-5-oxo-pentanoyl]amino]-5-oxo-pentanoyl]amino]-2-(9H-fluoren-9-ylmethoxycarbonylamino)hexanoic acid is dissolved in 20ml of dimethylformamide together with 310mg of hydroxybenzotriazol hydrate and 0,32ml of diisopropylcarbodiimide. After stirring of 5 minutes the solution is added to the resin. The resin is agitated for 20h and then washed 3 times with 20ml of dimethylformamide each. A small resin sample is taken and subjected to the Kaiser-test and the Chloranil-test (E. Kaiser, R. L. Colescott, C. D. Bossinger, P. I. Cook, Anal. Biochem. 1970, 34, 595-598; Chloranil-Test: T. Vojkovsky, ). This procedure avoids the need of a selective deprotection step as well as the selective attachment of the side chain building blocks on a very advanced synthesis intermediate.
-
column: Waters ACQUITY UPLC® CSH™ C18 1.7 µm (150 × 2.1mm) at 50 °C solvent: H2O+0.05%TFA : ACN+0.035%TFA (flow 0.5 ml/min) gradient: 80:20 (0 min) to 80:20 (3 min) to 25:75 (23 min) to 2:98 (23.5 min) to 2:98 (30.5 min) to 80:20 (31 min) to 80:20 (37 min) -
column: Waters ACQUITY UPLC® CSH™ C18 1.7 µm (150 × 2.1mm) at 50 °C solvent: H2O+0.05%TFA : ACN+0.035%TFA (flow 0.5 ml/min) gradient: 80:20 (0 min) to 80:20 (3 min) to 25:75 (23 min) to 2:98 (23.5 min) to 2:98 (30.5 min) to 80:20 (31 min) to 80:20 (37 min) -
column: Waters ACQUITY UPLC® CSH™ C18 1.7 µm (150 × 2.1mm) at 50 °C solvent: H2O+0.1%TFA : ACN+0.1%TFA (flow 0.5 ml/min) gradient: 80:20 (0 min) to 80:20 (3 min) to 25:75 (23 min) to 2:98 (23.5 min) to 2:98 (30.5 min) to 80:20 (31 min) to 80:20 (38 min) -
column: Waters ACQUITY BEH C18 (2.1×100 mm × 1.7 µm), Temp: 40 °C Aries peptide XB C18 (4.6x250 mm × 3.6 µm), Temp: 40 °C solvent: H2O+0.1%formic acid (buffer A) : ACN+0.1%formic acid (flow 1 ml/min) (buffer B) gradient: Equilibration of the column with 2 % buffer B and elution by a gradient of 2% to 70% buffer B during 15 min?? -
column: Waters ACQUITY UPLC® CSH™ C18 1.7 µm (150 × 2.1mm) at 50 °C solvent: H2O+0.05%TFA : ACN+0.035%TFA (flow 0.5 ml/min) gradient: 80:20 (0 min) to 80:20 (3 min) to 25:75 (23 min) to 5:95 (23.5 min) to 5:95 (25.5 min) to 80:20 (26 min) to 80:20 (30 min) - The crude peptides were purified either on an Äkta Purifier System, a Jasco semiprep HPLC System or a Agilent 1100 HPLC system. Preparative RP-C18-HPLC columns of different sizes and with different flow rates were used depending on the amount of crude peptide to be purified. Acetonitrile + 0.1% TFA (B) and water + 0.1% TFA (A) were employed as eluents. Product-containing fractions were collected and lyophilized to obtain the purified product, typically as TFA salt.
- Prior to the solubility measurement of a peptide batch, its purity was determined through UPLC/MS.
- For solubility testing the target concentration was 10mg pure compound/ml. Therefore solutions from solid samples were prepared in a buffer systems with a concentration of 10mg/mL compound based on the previously determined %purity:
- Solubility buffer system A) Acetate Buffer pH 4.5, 100mM sodium acetate trihydrate, 2.7mg/ml m-Cresol
- Solubility buffer system B) Phosphate Buffer pH 7.4, 100mM sodium hydrogen phosphate, 2.7mg/ml m-Cresol
- Solubility buffer system C) Citrate Buffer pH6.0, citric acid 100mM, 2,7mg/mL m-cresol
- UPLC-UV was performed after 1 hour of gentle agitation from the supernatant, which was obtained after 15min of centrifugation at 2500 RCF (relative centrifugal acceleration).
- The solubility was determined by the comparison of the UV peak area of 2µL-injection of a buffered sample diluted 1:10 with a standard curve of a reference peptide with known concentration. The different UV extinction coefficients of sample and reference peptide were calculated based on the different amino acid sequences and considered in the concentration calculation.
- Prior to the chemical stability measurement of a peptide batch, its purity was determined through UPLC/MS. For stability testing the target concentration was 1mg pure compound/ml. Therefore solutions from solid samples were prepared in a buffer system with a concentration of 1mg/mL compound based on the previously determined %purity:
- Chemical stability buffer system A) 25mM acetate buffer pH4.5, 3mg/mL L-Methionine, 2.7mg/mL m-cresol, 18mg/mL Glycerol 85%
- Chemical stability buffer system B) 25mM phosphate buffer pH6.0, 3mg/mL L-Methionine, 2.7mg/mL m-cresol, 18mg/mL Glycerol 85%
- Peptide solutions were filtered through 0.22µM pore size and filled into aliquots under aseptic conditions. At starting point UPLC-UV was performed by injection of 2µl of the undiluted sample.
- For chemical stability testing, aliquots were stored for 28 days at
5and 40°C. After this time course the samples were centrifuged for 15 min at 2500 RCF. Then 2µl of the undiluted supernatant were analysed with UPLC-UV. -
-
- A monochromatic and coherent light beam (laser) is used to illuminate the liquid sample. Dynamic Light Scattering (DLS) measures light scattered from particles (1nm ≤ radius ≤ 1µm) that undergo Brownian motion. This motion is induced by collisions between the particles and solvent molecules that themselves are moving due to their thermal energy. The diffusional motion of the particles results in temporal fluctuations of the scattered light [Pecora, R. Dynamic Light Scattering: Applications of Photon Correlation Spectroscopy, Plenum Press, 1985].
- The scattered light intensity fluctuations are recorded and transformed into an autocorrelation function. By fitting the autocorrelation curve to an exponential function, the diffusion coefficient D of the particles in solution can be derived. The diffusion coefficient is then used to calculate the hydrodynamic radius Rh (or apparent Stokes radius) through the Stokes-Einstein equation assuming spherical particles. This calculation is defined in ISO 13321 and ISO 22412 [International Standard ISO13321 Methods for Determination of Particle Size Distribution Part 8: Photon Correlation Spectroscopy, International Organisation for Standardisation (ISO) 1996; International Standard ISO22412 Particle Size Analysis - Dynamic Light Scattering, International Organisation for Standardisation (ISO) 2008].
- In case of polydisperse samples, the autocorrelation function is the sum of the exponential decays corresponding to each of the species. The temporal fluctuations of the scattered light can then be used to determine the size distribution profile of the particle fraction or family. The first order result is an intensity distribution of scattered light as a function of the particle size. The intensity distribution is naturally weighted according to the scattering intensity of each particle fraction or family. For biological materials or polymers the particle scattering intensity is proportional to the square of the molecular weight. Thus, small amount of aggregates/agglomerates or presence or a larger particle species can dominate the intensity distribution. However this distribution can be used as a sensitive detector for the presence of large material in the sample. The intensity distribution can be converted into a volume or mass distribution of the particle sizes using the Mie theory under certain assumptions. In contrast to the intensity distribution, the mass distribution is best used for comparative purposes and should never be considered absolute (due to the underlying assumptions).
- The DLS technique produces distributions with inherent peak broadening. The polydispersity index %Pd is a measure of the width of the particle size distribution and is calculated by standard methods described in ISO13321 and ISO22412 [International Standard ISO13321 Methods for Determination of Particle Size Distribution Part 8: Photon Correlation Spectroscopy, International Organisation for Standardisation (ISO) 1996; International Standard ISO22412 Particle Size Analysis - Dynamic Light Scattering, International Organisation for Standardisation (ISO) 2008].
- The DLS interaction parameter (kD) is a measure to describe inter-particle interactions, where the particles are folded proteins or peptides [Sandeep Yadav et al. (2009) J Pharm Sc, Vol 99(3), pp 1152-1168; Brian D. Connolly et al. (2012) Biophysical Journal Volume 103, pp 69-78].
-
- Neglecting the higher order terms, i.e. kiD = kjD = ... = 0, the data can be fitted linearly and kD is obtained from the slope of the curve D=D0 (1 +kDc) and D0. D0 is the diffusion coefficient at zero concentration. The parameter kD can be used to describe interaction of protein or peptide molecules or oligomers with their-self and their environment in solution and is theoretically related to the virial coefficient B22 as for example described by Harding and Johnson, where M is the molar mass, ks the first order concentration coefficient of sedimentation velocity and u the partial specific volume [Harding SE, Johnson P. (1985) Biochem J, 231, pp543-547].
- Positive B22 values indicate samples that favor salvation over self-association, while negative B22 values indicate samples that prefer self- association. From a pragmatic point of view, kD is analogous in its meaning to B22 and gives information on the net-forces between the molecules. High values indicate strong net-repulsive interactions, while low values indicate net-attractive forces. Therefore, kD can be used for relative, qualitative comparison (see
Figure 1 ). - For every peptide solution, the hydrodynamic radius Rh and the diffusion constant D (related via the Stokes-Einstein equation) were determined as an average over triplicates. Both parameters were determined at different concentrations (e.g., Rh1 and D1: 1 mg/ml and Rh5 and D5: 5 mg/ml) in the same buffer system. The difference of these parameters between low and high peptide concentration is a surrogate for the DLS interaction parameter kD. Rh5 < Rh1 or D5 > D1 correspond to kD > 0 and therefore to repulsive inter-particle interactions that result in improved physical (or colloidal) stability.
- DLS buffer system A) 25mM acetate buffer pH4.5, 3mg/mL L-Methionine, 2.7mg/mL m-cresol, 18mg/mL Glycerol 85%
- DLS buffer system B) 25mM phosphate buffer pH6.0, 3mg/mL L-Methionine, 2.7mg/mL m-cresol, 18mg/mL Glycerol 85%
- DLS Method A: DLS measurements were performed on a W130i apparatus (Avid Nano Ltd, High Wycombe, UK) and using a low-volume disposable cuvette (UVette, Eppendorf AG, Hamburg, Germany). The data were processed with i-Size 3.0 provided by Avid Nano. Parameters of the particle size distribution were determined with non-negatively constrained least squares (NNLS) methods using DynaLS algorithms. Measurements were taken at 25°C with a 660nm laser light source and at an angle of 90°.
- DLS Method B: DLS measurements were performed on a Nanosizer ZS (Malvern Instruments, Malvern, UK) and using disposible UV cuvettes (Brand macro , 2,5 mL and
Brand semi-micro - DLS Method C: DLS measurements were performed on a DynaPro Plate Reader II (Wyatt Technology, Santa Barbara, CA, US) and using one of the following black, low volume, and non-treated plates: polystyrene 384 assay plate with clear bottom (Corning, NY, US), polystyrene 96 assay plate with clear bottom (Corning, NY, US), cyclo olefin polymer (COP) 384 assay plate with clear bottom (Aurora, MT, US), or polystyrene 384 assay plate with clear bottom (Greiner Bio-One, Germany). The data were processed with the Dynamics software provided by Wyatt Technology. Parameters of the particle size distribution were determined with non-negatively constrained least squares (NNLS) methods using DynaLS algorithms. Measurements were taken at 25°C with an 830 nm laser light source at an angle of 158°.
- Low physical stability of a peptide solution may lead to amyloid fibril formation, which is observed as well-ordered, thread-like macromolecular structures in the sample, which eventually may lead to gel formation. Thioflavin T (ThT) is widely used to visualize and quantify the presence of misfolded protein aggregates.[Biancalana et al. (2010) Biochimica et Biophysica Acta. 1804 (7): 1405-1412.]. When it binds to fibrils, such as those in amyloid aggregates, the dye displays a distinct fluorescence signature [Naiki et al. (1989)Anal. Biochem.177, 244-249; LeVine (1999) Methods. Enzymol. 309, 274-284]. The time course for fibril formation often follows the characteristic shape of a sigmoidal curve and can be separated into three regions: a lag phase, a fast growth phase, and a plateau phase.
- The typical fibril formation process starts with the lag phase in which the amount of partially folded peptide turned into fibrils is not significant enough to be detected. The lag-time corresponds to the time the critical mass of the nucleus is built. Afterwards, a drastic elongation phase follows and fibril concentration increases rapidly.
- Investigations were carried out to determine fibrillation tendencies under stress conditions by shaking at 37°C within Fluoroskan Ascent FL.
- For the tests in Fluoroskan Ascent FL, 200 µL sample were placed into a 96 well mictrotiter plate PS, flat bottom, Greiner Fluotrac No. 655076. Plates were sealed with Scotch Tape (Quiagen). Samples were stressed by continuous cycles of 10 s shaking at 960 rpm and 50 s rest period at 37°C. The kinetic was monitored by measuring fluorescence intensity every 20 minutes.
- Peptides were diluted in a buffer system to a final concentration of 3 mg/ml. 20µL of a 10.1 mM ThT solution in H2O were added to 2 mL of peptide solution to receive a final concentration of 100 µM ThT. For each sample eight replicates were tested.
- Tht buffer system A) 100 mM Acetate pH 4.5 including m-cresol (100 mM Natriumacetat trihydrat, pH adjustment using 2N CH3COOH, 2. 7 mg/mL m-cresol) Tht buffer system B) 100 mM citrate buffer pH 6.0
- In vitro cellular assays for GLP-1, glucagon and GIP receptor efficacy Agonism of compounds for the receptors was determined by functional assays measuring cAMP response of HEK-293 cell lines stably expressing human GLP-1, GIP or glucagon receptor.
- cAMP content of cells was determined using a kit from Cisbio Corp. (cat. no. 62AM4PEJ) based on HTRF (Homogenous Time Resolved Fluorescence). For preparation, cells were split into T175 culture flasks and grown overnight to near confluency in medium (DMEM / 10% FBS). Medium was then removed and cells washed with PBS lacking calcium and magnesium, followed by proteinase treatment with accutase (Sigma-Aldrich cat. no. A6964). Detached cells were washed and resuspended in assay buffer (1 × HBSS; 20 mM HEPES, 0.1% BSA, 2 mM IBMX) and cellular density determined. They were then diluted to 400000 cells/ml and 25 µl-aliquots dispensed into the wells of 96-well plates. For measurement, 25 µl of test compound in assay buffer was added to the wells, followed by incubation for 30 minutes at room temperature. After addition of HTRF reagents diluted in lysis buffer (kit components), the plates were incubated for 1 hr, followed by measurement of the fluorescence ratio at 665 / 616 nm. In vitro potency of agonists was quantified by determining the concentrations that caused 50% activation of maximal response (EC50).
- Mice were dosed 1 mg/kg subcutaneously (s.c.). The mice were sacrified and blood samples were collected after 0.25, 0.5, 1, 2, 4, 8, 16 and 24 hours post application. Plasma samples were analyzed after protein precipitation via liquid chromatography mass spectrometry (LC/MS). PK parameters and half-life were calculated using WinonLin Version 5.2.1 (non-compartment model).
- Female Göttinger minipigs were dosed 0.05 mg/kg, 0.075 mg/kg or 0.1 mg/kg subcutaneously (s.c.). Blood samples were collected after 0.25, 0.5, 1, 2, 4, 8, 24, 32, 48, 56 and 72 hours post application. Plasma samples were analyzed after protein precipitation via liquid chromatography mass spectrometry (LC/MS). PK parameters and half-life were calculated using WinonLin Version 5.2.1 (non-compartment model).
- Female C57BL/6NHsd mice were ordered group housed from Envigo RMS Inc., shipped group housed and remained group housed with shipped cage mates in shoebox caging with wood chip bedding until day 38 of the predose phase. At the study start mice were between 25-26 weeks old.
- Mice were housed under vivarium conditions that included a 12 h light/dark cycle (light phase 04:00 AM - 4:00 PM), room temperatures between 23 - 26°C and a relative humidity between 30 - 70%. All animals had free access to water and a high fat diet (TD97366) for 16 weeks prior to pharmacological intervention (dosing phase).
- Feed was replaced with fresh feed weekly until and for the last time on day 38 of the predose phase. During the subsequent dosing phase, approximately 50% of the remaining feed were removed, replaced with fresh feed, and pellets were mixed evenly once per week.
- On predose day 38, obese DIO mice were assigned to treatment groups (n = 8) to match mean body masses between all DIO groups. An age-matched group with ad libitum access to a rodent maintenance diet (Teklad Global Diets Rodent 2014, pelleted) was included in the study as a lean control group. In the predosing phase from day 32 through 38, all study animals were treated with vehicle (Phosphate Buffered Saline, PBS, Gibco, without CaCl2 and MgCl2) once daily (s.c. approximately 0.2 mL/mouse).
- On day 37 of the predose phase, the test article was diluted with PBS to a concentration of 100 µg/mL and aliquots of this stock solution were stored at approximately ≤-60°C. Stock aliquots were thawed for weekly use and thereafter stored in a refrigerator at approximately 4°C. The injected test article solution was prepared fresh once on each dosing day by diluting stock solution with PBS to achieve the desired concentration.
- Mice were treated twice daily with a s.c. injection of PBS-vehicle or the test article for 28 days. The morning dosing was initiated and completed between 06:00 and 07:30 AM and the afternoon dosing between 2:00 and 3:30 PM. On
day 28 of the dosing phase only the morning dose was administered. The applied volume was 5 ml/kg and the dose was adjusted to the most recent body mass recording of each individual. - 1) Acute effect on blood glucose profiles in fed, female DIO mice:
Animals had unlimited access to water and feed during the experiment. Onday 1 of the dosing phase approximately 5 µL of blood were collected via tail clips athour 0, prior to the first s.c. dose of PBS-vehicle or test-article as well as 1, 2, 3, 4, 6, and 24 hours post-dose. Animals received the second s.c. dose of PBS-vehicle or test-article 8 hours after the first dose. The 24 hour blood collection of the blood glucose profile was performed prior to dosing onday 2. Glucose measurements were performed in whole blood and in duplicate or triplicate using Aviva glucometers. - 2) Chronic effect on body mass in fed, female DIO mice:
Body mass was measured daily approximately between 06:00-07:30 AM from day 32 through 38 of the predosing phase and throughout the 28 days of the dosing phase. During the dosing phase mice were treated twice daily with either a s.c. injection of PBS-vehicle or test article. - 3) Chronic effect on whole body fat mass in fed, female DIO mice:
To determine whole body fat mass Quantitative Nuclear Magnetic Resonance (QNMR) measurements were performed on predosing day 37 and onday 26 of the dosing phase. During the dosing phase mice were treated twice daily with either a s.c. injection of PBS-vehicle or test article. - 4) Effect on feed consumption in female DIO mice:
Feed consumption was based on the daily assessment of the feeder weights of each cage between 06:00-07:30 AM. Each cage housed four mice and feed consumption was calculated throughout the 28 days of the dosing phase. During the dosing phase mice were treated twice daily with either a s.c. injection of PBS-vehicle or test article. - 5) Terminal plasma parameters in non-fasting, female DIO mice:
Onday 28 blood was collected prior to any other inlife activities for determination of plasma insulin concentrations. Then the morning dose was administered and necropsy was performed 4 hours post-dose. For this purpose animals were anesthetized with isoflurane and blood was collected by orbital bleeding. - 5) Terminal liver mass in non-fasting, female DIO mice:
Onday - 6) Quantification of liver lipids
Liver aliquots were incubated with dichlormethane : methanol (2 :1). The lipohilic and lipohobic phase were separated by adding dH2O and subsequent centrifugation. The bottom lipophilic phase was collected and the procedure repeated with the remaining lipophobic layer and liver tissue. Next the lipophilic phases were combined and the solvent evaporated. At 60°C and continuous shaking samples were then incubated with 2-propanol. Total cholesterol, triacylglycerol and phospholipid concentrations were quantified enzymatically with a commercial kit according to the manufacturer's instructions. - 7) Statistical analyses:
- Data are depicted as means±SEM. Statistical analyses were performed with Sigmaplot 12.5. A One-Way ANOVA and Tukey Test were used for pairwise multiple comparisons of all groups (n=8/group, deviations from group size are indicated).
- When the difference in the mean values of the two groups was greater than 0.05 they were considered statistically significantly different. Lean-Vehicle group data serve as a reference dataset for the non-obese state.
- Female healthy, lean BKS.Cg-(lean)/OlaHsd and diabetes-prone, obese BKS.Cg-+Leprdb/+Leprdb/OlaHsd mice were ordered group housed from Envigo RMS Inc., shipped group housed and remained group housed in shoebox caging with wood chip bedding until
day 15 of the predose phase. At the study start mice were approximately 12 weeks old. - Mice were housed under vivarium conditions including a 12 h light/dark cycle (light phase 04:00 AM - 4:00 PM), room temperatures between 23 - 26°C and a relative humidity between 30 - 70%. All animals had free access to water and Purina Fomulab Diet 5008.
- On
predose day 9 blood glucose and body mass (approximately between 08:00 - 10:00 AM) as well as HbA1c measurements were performed. Onday 15 of the predose phase animals were assigned to treatment groups (n = 8) and to new cages to match mean HbA1c and body masses between all db/db groups. An age-matched lean group was included in the study as a healthy, lean reference. - Prior to
day 1 of the dosing phase, the test article was diluted with Phosphate Buffered Saline (PBS, Gibco, without CaCl2 and MgCl2) to a concentration of 1 mg/mL and aliquots of this stock solution were stored at approximately ≤-60°C. Onday 1 of the dosing phase the stock aliquot was thawed and the injected test article solution was prepared fresh by diluting it with PBS to achieve the desired concentration. - On
Day 1 of the dosing phase db/db mice were either treated once with a s.c. injection of PBS-vehicle or 30 µg/kg test article. The lean reference group was treated once with a s.c. injection of PBS-vehicle. The dosing was initiated and completed between 08:00 and 10:00 AM. The applied volume was 5 ml/kg and the dose was adjusted to the most recent body mass recording of each individual. - 1) Acute effect on blood glucose profiles in non-fasting animals:
Animals had unlimited access to water and feed during the experiment. Onday 1 of the dosing phase approximately 5 µL of blood were collected via tail clips at minute -30 and 0 prior to any other inlife activities. Atminute 0 mice received a s.c. dose of either PBS-vehicle or 30 µg/kg test article. Further blood samples were harvested at hour 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 post-dose. Glucose measurements were performed in whole blood using AlphaTRAK glucometers. If the glucose concentrations of two measurements differed by more than 20 mg/dL a third value was recorded. The Area Under the Curve (AUC) for blood glucose was calculated via the trapezoid method and for the duration of the 24 post-dose hours. - 2) Statistical analyses:
- 3) Data are depicted as means±SEM. Statistical analyses were performed with Sigmaplot 12.5. A One-Way ANOVA and Tukey Test were used for pairwise multiple comparisons of all groups (n=8/group, deviations from group size are indicated). When the difference in the mean values of the two groups was greater than 0.05 they were considered statistically significantly different. Data from a Non-Diabetic-Vehicle group serve as a reference dataset for the normoglycemic,, lean state.
- The invention is further illustrated by the following examples.
- Synthesis of SEQ ID NO: 6
- The solid phase synthesis as described in Methods was carried out on Novabiochem Rink-Amide resin (4-(2',4'-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucylaminomethyl resin), 100-200 mesh, loading of 0.43 mmol/g. The Fmoc-synthesis strategy was applied with HBTU/DIPEA-activation. In
position 14 Fmoc-Lys(Mmt)-OH and inposition 1 Boc-His(Trt)-OH were used in the solid phase synthesis protocol The Mmt-group was cleaved from the peptide on resin as described in the Methods. Hereafter Palm-gGlu-gGlu-OSu was coupled to the liberated amino-group employing DIPEA as base. The peptide was cleaved from the resin with King's cocktail (D. S. King, C. G. Fields, G. B. Fields, Int. J. Peptide Protein Res. 1990, 36, 255-266). The crude product was purified via preparative HPLC on a Waters column (Sunfire Prep C18 ODB 5µm 50x150mm) using an acetonitrile/water gradient (both buffers with 0,1% TFA). The purified peptide was analysed by LCMS (Method B). - Deconvolution of the mass signals found under the peak with retention time 9.824 min revealed the peptide mass 4839.67 which is in line with the expected value of 4839.67.
- Synthesis of SEQ ID NO: 7
- The solid phase synthesis as described in Methods was carried out on Novabiochem Rink-Amide resin (4-(2',4'-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucylaminomethyl resin), 100-200 mesh, loading of 0.43 mmol/g. The Fmoc-synthesis strategy was applied with HBTU/DIPEA-activation. In
position 14 Fmoc-Lys(Mmt)-OH and inposition 1 Boc-His(Trt)-OH were used in the solid phase synthesis protocol. The Mmt-group was cleaved from the peptide on resin as described in the Methods. Hereafter Palm-gGlu-gGlu-OSu was coupled to the liberated amino-group employing DIPEA as base. The peptide was cleaved from the resin with King's cocktail (D. S. King, C. G. Fields, G. B. Fields, Int. J. Peptide Protein Res. 1990, 36, 255-266). The crude product was purified via preparative HPLC on a Waters column (Sunfire Prep C18 OBD 5µm 50x150mm) using an acetonitrile/water gradient (both buffers with 0,1% TFA). The purified peptide was analysed by LCMS (Method B). - Deconvolution of the mass signals found under the peak with retention time 9.935 min revealed the peptide mass 4853.73 which is in line with the expected value of 4853.67.
- Synthesis of SEQ ID NO: 11
- The solid phase synthesis as described in Methods was carried out on Novabiochem Rink-Amide resin (4-(2',4'-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamido-norleucylaminomethyl resin), 100-200 mesh, loading of 0.43 mmol/g. The Fmoc-synthesis strategy was applied with HBTU/DIPEA-activation. In
position 14 Fmoc-Lys(Mmt)-OH and inposition 1 Boc-His(Trt)-OH were used in the solid phase synthesis protocol. The Mmt-group was cleaved from the peptide on resin as described in the Methods. Hereafter Palm-gGlu-gGlu-OSu was coupled to the liberated amino-group employing DIPEA as base. The peptide was cleaved from the resin with King's cocktail (D. S. King, C. G. Fields, G. B. Fields, Int. J. Peptide Protein Res. 1990, 36, 255-266). The crude product was purified via preparative HPLC on a Waters column (Sunfire Prep C18 OBD 5µm 50x150mm) using an acetonitrile/water gradient (both buffers with 0,1% TFA). The purified peptide was analysed by LCMS (Method B). - Deconvolution of the mass signals found under the peak with retention time 9.828 min revealed the peptide mass 4894.63 which is in line with the expected value of 4894.64.
- In an analogous way, the other peptides listed in Table 3 were synthesized and characterized.
Table 3: list of synthesized peptides and comparison of calculated vs. found molecular weight SEQ ID NO calc. Mass found mass Monoisotopic or average mass Retention time (min) 6 4839.7 4839.7 monoisotopic 9.824 7 4853.7 4853.7 monoisotopic 9.935 8 4880.6 4880.6 monoisotopic 9.585 9 4840.6 4840.6 monoisotopic 10.471 10 4854.6 4854.7 monoisotopic 10.64 11 4894.6 4849.6 monoisotopic 9.828 12 4879.7 4879.7 monoisotopic 9.490 13 4893.7 4893.7 monoisotopic 9.690 14 4710.6 4710.7 monoisotopic 9.435 15 4738.7 4783.7 monoisotopic 10.528 16 5024.7 5024.7 monoisotopic 9.137 17 5038.8 5038.8 monoisotopic 9.286 18 5025.7 5025.7 monoisotopic 9.573 19 5039.7 5039.7 monoisotopic 9.715 20 5041.8 5040.8 average 8.996 21 5055.8 5055.0 average 9.102 22 5042.8 5041.6 average 9.254 23 5056.8 5055.6 average 9.340 - Peptide samples were prepared in Chemical stability buffer system A and chemical stability was assessed as described in Methods. The results are given in Table 4.
Table 4: Stability SEQ ID NO Chemical stability [ relative purity loss 28days 40°C] (%) at pH4.56 6.9 7 6.8 8 7.6 9 8.7 10 7.4 11 7.2 12 5.4 13 4.5 14 5.5 15 5.6 17 6.4 19 6.0 23 9.6 - Peptide samples were prepared in solubility buffer system A and solubility was assessed as described in Methods. The results are given in Table 5.
Table 5: Solubility SEQ ID NO Solubility [mg/ml] at pH4.5 6 >9,6 7 >9,9 8 >10 10 >10,1 11 >9,9 12 >9,3 13 >9,3 14 >9,3 15 >8,9 17 >9,2 19 >9,2 23 >10,4 - The hydrodynamic radius radius Rh of peptide samples was determined at different peptide concentrations (1 mg/ml and 5 mg/ml) in DLS buffer system A using DLS method C as described in Methods as surrogate for the DLS interaction parameter kD. The results are given in Table 6.
- Table 6: hydrodynamic radius Rh at peptide concentrations of 1 mg/ml and 5 mg/ml. A decrease of Rh at the higher peptide concentration indicates higher physical stability due to repulsive inter-particle interactions.
SEQ. ID Rh1 [nm] c = 1mg/ml Rh5 [nm] c = 5mg/ml Delta Rh [nm] = Rh5 - R h16 2.3 1.8 -0.5 7 2.8 2.4 -0.3 13 2.8 2.5 -0.3 14 2.7 2.4 -0.2 15 2.7 2.6 -0.2 17 2.9 2.4 -0.5 19 3.1 3.0 -0.1 23 2.8 2.7 -0.1 - Lag time in hours in Thioflavin T (ThT) assay of peptide samples was determined in Tht buffer system A as described in Methods. The results are given in Table 7.
Table 7: Lag time in hours in Thioflavin T (ThT) assay SEQ ID NO Increase in FI at pH 4.5 Lag time before increase [h] 6 NO >45 7 NO >45 8 NO >45 9 NO >45 10 NO >45 11 NO >45 12 NO >45 13 NO >45 16 NO >45 17 NO >45 18 NO >45 19 NO >45 20 NO >45 21 NO >45 22 NO >45 23 NO >45 - Potencies of peptidic compounds at the GLP-1, glucagon and GIP receptors were determined by exposing cells expressing human glucagon receptor (hGlucagon R), human GIP receptor (hGIP-R) or human GLP-1 receptor (hGLP-1 R) to the listed compounds at increasing concentrations and measuring the formed cAMP as described in Methods.
- The results are shown in Table 8.
Table 8. EC50 values of exendin-4 derivatives at human GLP-1, Glucagon and GIP receptors (indicated in pM) SEQ ID NO EC50 hGLP-1R EC50 hGlucagon R EC50 hGIP R 6 2.8 16.4 7.9 7 4.0 21.8 14.2 8 2.2 32.6 5.6 9 2.6 24.7 5.6 10 2.4 26.1 5.4 11 2.3 22.4 3.5 12 2.7 22.0 15.8 13 3.8 25.8 20.4 14 5.7 31.6 18.2 15 5.7 15.6 26.1 16 1.3 18.6 7.5 17 1.8 22.0 11.4 18 1.7 46.6 5.6 19 1.9 52.2 7.9 20 2.4 44.0 12.7 21 4.2 69.9 24.6 22 2.1 108.0 6.0 23 1.0 64.3 2.0 - Lean and diet-induced obese, 25-26 weeks old, female C57BL/6NHsd mice were treated twice daily with a s.c. injection of PBS, 30 µg/kg SEQ ID NO: 6, or 30 µg/kg SEQ ID NO: 7 for 28 days. The morning dosing was initiated and completed between 06:00 and 07:30 AM and the afternoon dosing between 14:00 and 15:30 PM. The applied volume was 5 ml/kg and the dose was adjusted to the most recent body mass recording of each individual.
- Animals had unlimited access to water and feed during the experiment. On
day 1 of the dosing phase approximately 5 µL of blood were collected via tail clips athour 0, prior to the first s.c. dose of PBS-vehicle, 30 µg/kg SEQ ID NO: 6, or 30 µg/kg SEQ ID NO: 7, as well as 1, 2, 3, 4, 6, and 24 hours post-dose. Animals received the second s.c. dose of PBS-vehicle, 30 µg/kg SEQ ID NO: 6, or 30 µg/kg SEQ ID NO: 7 8 hours after the first dose. The 24 hour blood collection of the blood glucose profile was performed prior to dosing onday 2. Glucose measurements were performed in whole blood and in duplicate or triplicate using Aviva glucometers. Both, 30 µg/kg SEQ ID NO: 6 and 30 µg/kg SEQ ID NO: 7 mediated a comparable decrease in blood glucose concentrations below concentrations observed in DIO control mice during the 24 hour blood glucose profile (Figure 2 ). - Chronic, twice daily treatment with SEQ ID NO: 6, or SEQ ID NO: 7 resulted in a body mass reduction within the 28 days of the dosing phase in contrast to animals of the DIO-vehicle group (
Figure 3 ). Chronic treatment of DIO animals with 30 µg/kg SEQ ID NO: 6, or SEQ ID NO: 7 induced a statistically significant decrease in body mass compared to the DIO-Vehicle group (One-Way ANOVA and Tukey Test,Figure 4 , Table 9). - Whole body fat mass was determined via Nuclear Magnetic Resonance (QNMR) once in the predosing phase and once on
day 26 of the dosing phase daily. In the dosing phase mice were treated twice daily with either a s.c. injection of PBS-vehicle, 30 µg/kg SEQ ID NO: 6, or 30 µg/kg SEQ ID NO: 7. - Chronic, twice daily treatment with SEQ ID NO: 6 and SEQ ID NO: 7 resulted in a statistically significantly reduction in whole body fat mass within the 28 days compared to the DIO-Vehicle group (One-Way ANOVA and Tukey Test,
Figure 5 , Table 9). - On
day 28 mice were euthanized 4 hours after the morning dose and livers were collected. - Twice-daily, chronic treatment of DIO animals with 30 µg/kg SEQ ID NO: 6, or 30 µg/kg SEQ ID NO: 7 resulted in a statistically significantly lower liver mass on
day 28 of the dosing phase compared to DIO animals treated with vehicle (One-Way ANOVA and Tukey Test,Figure 6 , Table 9). - On
day - Twice-daily, chronic treatment of DIO animals with 30 µg/kg SEQ ID NO: 6 or 30 µg/kg SEQ ID NO: 7 resulted in a statistically significanty lower plasma alanine aminotransferase concentration on
day 28 of the dosing phase compared to DIO animals treated with vehicle suggesting improvement of liver function (One-Way ANOVA and Tukey Test,Figure 7 , Table 9). - On
day - Twice-daily, chronic treatment of DIO animals with 30 µg/kg SEQ ID NO: 6 or 30 µg/kg SEQ ID NO: 7 resulted in a statistically significant reduction in plasma total cholesterol concentrations compared to DIO animals treated with vehicle (One-Way ANOVA and Tukey Test,
Figure 8 , Table 9). - On
day - Twice-daily, chronic treatment of DIO animals with 30 µg/kg SEQ ID NO: 6 or 30 µg/kg SEQ ID NO: 7 resulted in a statistically significant reduction in plasma insulin concentrations compared to DIO animals treated with vehicle hinting towards an improvement of high fat-diet induced insulin resistance (One-Way ANOVA and Tukey Test,
Figure 9 , Table 9). - Data are depicted as means±SEM. Statistical analyses were performed with Sigmaplot 12.5. A One-Way ANOVA and Tukey Test was used for pairwise multiple comparisons of all groups (as indicated n=7-8/group). When the difference in the mean values of the two groups was greater than 0.05 they were considered statistically significantly different. Lean-Vehicle group data are depicted in the Figures serving as a reference dataset for the non-obese state.
Table 9. Effects resulting from a 28 days qd dosing study with SEQ ID NO: 6 and SEQ ID NO: 7 in fed, female diet-induced obese (DIO) C57BL/6 mice. Data are means±SEM. One-Way ANOVA and Tukey Test, n=8/group except n=7 DIO-Vehicle. Example Dose DIO-Vehicle twice-daily PBS DIO-SEQ ID NO: 6 twice-daily 30 µg/kg DIO-SEQ ID NO: 7 twice-daily 30 µg/kg Body mass change (g) 4.65 ± 0.33 - 5.36 ± 0.36 P<0.001 vs. DIO-Vehicle - 5.58 ± 0.60 P<0.001 vs. DIO-Vehicle Whole body fat mass change (g) 3.37 ± 0.36 -4.33 ± 0.42 P<0.001 vs. DIO-Vehicle -4.46 ± 0.50 P<0.001 vs. DIO-Vehicle Terminal liver mass (g) +1.94 ± 0.11 +1.16 ± 0.04 P<0.001 vs. DIO-Vehicle +1.14 ± 0.04 P<0.001 vs. DIO-Vehicle Terminal plasma alanine aminotransferase (U/L) +155.25 ± 13.46 +62.25 ± 9.79 P<0.001 vs. DIO-Vehicle +47.63 ± 6.76 P<0.001 vs. DIO-Vehicle Terminal plasma total cholesterol (mmol/L) +2.27 ± 0.09 +5.11 ± 0.12 P<0.001 vs. DIO-Vehicle +4.19 ± 0.15 P<0.001 vs. DIO-Vehicle Terminal plasma insulin (U/L) +217.94 ± 51.48 +31.07 ± 5.26 P<0.001 vs. DIO-Vehicle +58.04 ± 6.33 P<0.001 vs. DIO-Vehicle - Female, 12 weeks old, healthy, lean BKS.Cg-(lean)/OlaHsd or diabetes-prone, obese BKS.Cg-+Leprdb/+Leprdb/OlaHsd mice were treated once with a s.c. injection of PBS, 30 µg/kg SEQ ID NO: 6 or 30 µg/kg SEQ ID NO: 7. The dosing was initiated and completed between 08:00 and 10:00 AM. The applied volume was 5 ml/kg and the dose was adjusted to the most recent body mass recording of each individual. Diabetic db/db mice were HbA1c- and body mass-matched. The lean reference group was treated once with a s.c. injection of PBS-vehicle.
- Animals had unlimited access to water and feed during the experiment. On
day 1 of the dosing phase approximately 5 µL of blood were collected via tail clips at minute -30 and 0 prior to any other inlife activities. Atminute 0 mice received a s.c. dose of either PBS-vehicle, 30 µg/kg SEQ ID NO: 6 or SEQ ID NO: 7. Further blood samples were harvested atminute - SEQ ID NO: 6 or SEQ ID NO: 7 treated animals exhibited a comparable, acute decrease in blood glucose concentrations and reached lowest levels approximately 8 hours post dose (
Figure 10 ). Twentyfour hours post-dose mean blood glucose concentrations of all treated animals were at or close to baseline (Figure 10 ). Single treatment of diabetic db/db mice with 30 µg/kg SEQ ID NO: 6 or 30 µg/kg SEQ ID NO: 7 resulted in a statistically significant reduction in the blood glucose AUC compared to the Diabetic-Vehicle group (One-Way ANOVA and Tukey Test,Figure 11 , Table 10). - Data are depicted as means±SEM. Statistical analyses were performed with Sigmaplot 12.5. A One-Way ANOVA and Tukey Test was used for pairwise multiple comparisons of all groups (n=8/group). When the difference in the mean values of the two groups was greater than 0.05 they were considered statistically significantly different. Lean-Vehicle group data are depicted in the Figures serving as a reference dataset for the non-obese state.
Table 10. Effects resulting from a single dose SEQ ID NO: 6 or SEQ ID NO: 7 in fed, female db/db mice. Data are means±SEM. One-Way ANOVA and Tukey Test. n=8/group. Example Dose Diabetic-Vehicle Once PBS DIO-SEQ ID NO: 6 Once 30 µg/kg DIO-SEQ ID NO: 7 Once 30 µg/kg Plasma glucose area under the curve (mmol/L in 24 h) +705.52 ± 49.31 +430.70 ± 26.41 P<0.001 vs. Diabetic-Vehicle +461.54 ± 39.43 P<0.001 vs. Diabetic-Vehicle - Lean and diet-induced obese, 25-26 weeks old, female C57BL/6NHsd mice were treated twice daily with a s.c. injection of PBS, 30 µg/kg SEQ ID NO: 8, 30 µg/kg SEQ ID NO: 9, or 30 µg/kg SEQ ID NO: 10 for 28 days. The morning dosing was initiated and completed between 06:00 and 07:30 AM and the afternoon dosing between 14:00 and 15:30 PM. The applied volume was 5 ml/kg and the dose was adjusted to the most recent body mass recording of each individual.
- Animals had unlimited access to water and feed during the experiment. On
day 1 of the dosing phase approximately 5 µL of blood were collected via tail clips athour 0, prior to the first s.c. dose of PBS-vehicle, 30 µg/kg SEQ ID NO: 8, 30 µg/kg SEQ ID NO: 9, or 30 µg/kg SEQ ID NO: 10 as well as 1, 2, 3, 4, 6, and 24 hours post-dose. Animals received the second s.c. dose of PBS-vehicle, 30 µg/kg SEQ ID NO: 8, 30 µg/kg SEQ ID NO: 9, or 30 µg/kg SEQ ID NO: 10 8 hours after the first dose. The 24 hour blood collection of the blood glucose profile was performed prior to dosing onday 2. Glucose measurements were performed in whole blood and in duplicate or triplicate using Aviva glucometers. - 30 µg/kg SEQ ID NO: 8, 30 µg/kg SEQ ID NO: 9, or 30 µg/kg, and SEQ ID NO: 10 mediated a comparable decrease in blood glucose concentrations below concentrations observed in DIO control mice during the 24 hour blood glucose profile (
Figure 12 ). - Body mass was determined daily. In the dosing phase mice were treated twice daily with either a s.c. injection of PBS-vehicle, 30 µg/kg SEQ ID NO: 8, 30 µg/kg SEQ ID NO: 9, or 30 µg/kg SEQ ID NO: 10.
- Chronic, twice daily treatment with SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10 resulted in a body mass reduction within the 28 days of the dosing phase in contrast to animals of the DIO-vehicle group (
Figure 13 ). Chronic treatment of DIO animals with 30 µg/kg SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10 induced a statistically significant decrease in body mass compared to the DIO-Vehicle group (One-Way ANOVA and Tukey Test,Figure 14 , Table 11). - Whole body fat mass was determined via Nuclear Magnetic Resonance (QNMR) once in the predosing phase and once on
day 26 of the dosing phase daily. In the dosing phase mice were treated twice daily with either a s.c. injection of PBS-vehicle, 30 µg/kg SEQ ID NO: 8, 30 µg/kg SEQ ID NO: 9, or 30 µg/kg SEQ ID NO: 10. Chronic, twice daily treatment with SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO resulted in a statistically significantly reduction in whole body fat mass within the 28 days compared to the DIO-Vehicle group (One-Way ANOVA and Tukey Test,Figure 15 , Table 11). - On
day 28 mice were euthanized 4 hours after the morning dose and livers were collected. - Twice-daily, chronic treatment of DIO animals with 30 µg/kg SEQ ID NO: 8, 30 µg/kg SEQ ID NO: 9, or 30 µg/kg SEQ ID NO: 10 resulted in a statistically significantly lower liver mass on
day 28 of the dosing phase compared to DIO animals treated with vehicle (One-Way ANOVA and Tukey Test,Figure 16 , Table 11). - On
day - Twice-daily, chronic treatment of DIO animals with 30 µg/kg SEQ ID NO: 8, 30 µg/kg SEQ ID NO: 9, or 30 µg/kg SEQ ID NO: 10 resulted in a statistically significanty lower plasma alanine aminotransferase concentration on
day 28 of the dosing phase compared to DIO animals treated with vehicle suggesting improvement of liver function (One-Way ANOVA and Tukey Test,Figure 17 , Table 11). - On
day - Twice-daily, chronic treatment of DIO animals with 30 µg/kg SEQ ID NO: 8, 30 µg/kg SEQ ID NO: 9, or 30 µg/kg SEQ ID NO: 10 resulted in a statistically significant reduction in plasma total cholesterol concentrations compared to DIO animals treated with vehicle (One-Way ANOVA and Tukey Test,
Figure 18 , Table 11). - On
day - Twice-daily, chronic treatment of DIO animals with 30 µg/kg SEQ ID NO: 8, 30 µg/kg SEQ ID NO: 9, or 30 µg/kg SEQ ID NO: 10 resulted in a statistically significant reduction in plasma insulin concentrations compared to DIO animals treated with vehicle hinting towards an improvement of high fat-diet induced insulin resistance (One-Way ANOVA and Tukey Test,
Figure 19 , Table 11). - Data are depicted as means±SEM. Statistical analyses were performed with Sigmaplot 12.5. A One-Way ANOVA and Tukey Test was used for pairwise multiple comparisons of all groups (as indicated n=7-8/group). When the difference in the mean values of the two groups was greater than 0.05 they were considered statistically significantly different. Lean-Vehicle group data are depicted in the Figures serving as a reference dataset for the non-obese state.
Table 11. Effects resulting from a 28 days qd dosing study with SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10 in fed, female diet-induced obese (DIO) C57BL/6 mice. Data are means±SEM. One-Way ANOVA and Tukey Test, n=8/group. Example Dose DIO-Vehicle twice-daily PBS DIO-SEQ ID NO: 8 twice-daily 30 µg/kg DIO-SEQ ID NO: 9 twice-daily 30 µg/kg DIO-SEQ ID NO: 10 twice-daily 30 µg/kg Body mass change (g) 5.10 ± 0.49 - 8.23 ± 0.62 P<0.001 vs. DIO-Vehicle - 10.03 ± 2.33 P<0.001 vs. DIO-Vehicle - 7.14 ± 0.64 P<0.001 vs. DIO-Vehicle Whole body fat mass change (g) 2.51 ± 0.65 -6.65 ± 0.38 P<0.001 vs. -5.29 ± 2.32 P<0.001 vs. -6.48 ± 0.90 P<0.001 vs. DIO-Vehicle DIO-Vehicle DIO-Vehicle Terminal liver mass (g) +1.80 ± 0.07 +1.08 ± 0.03 P<0.001 vs. DIO-Vehicle +1.11 ± 0.06 P<0.001 vs. DIO-Vehicle +1.07 ± 0.04 P<0.001 vs. DIO-Vehicle Terminal plasma alanine aminotransferase (U/L) 207.50 ± 14.98 +68.88 ± 15.05 P<0.001 vs. DIO-Vehicle +57.13 ± 7.33 P<0.001 vs. DIO-Vehicle +56.75 ± 4.65 P<0.001 vs. DIO-Vehicle Terminal plasma total cholesterol (mmol/L) +5.45 ± 0.15 +4.36 ± 0.08 P<0.001 vs. DIO-Vehicle +3.97 ± 0.12 P<0.001 vs. DIO-Vehicle +4.28 ± 0.15 P<0.001 vs. DIO-Vehicle Terminal plasma insulin (U/L) +145.08 ± 29.15 +39.70 ± 4.25 P<0.001 vs. DIO-Vehicle +38.95 ± 7.30 P<0.001 vs. DIO-Vehicle +35.81 ± 2.79 P<0.001 vs. DIO-Vehicle - Female, 12 weeks old, healthy, lean BKS.Cg-(lean)/OlaHsd or diabetes-prone, obese BKS.Cg-+Leprdb/+Leprdb/OlaHsd mice were treated once with a s.c. injection of PBS or30 µg/kg SEQ ID NO: 13. The dosing was initiated and completed between 08:00 and 10:00 AM. The applied volume was 5 ml/kg and the dose was adjusted to the most recent body mass recording of each individual. Diabetic db/db mice were HbA1c- and body mass-matched. The lean reference group was treated once with a s.c. injection of PBS-vehicle.
- Animals had unlimited access to water and feed during the experiment. On
day 1 of the dosing phase approximately 5 µL of blood were collected via tail clips at minute -30 and 0 prior to any other inlife activities. Atminute 0 mice received a s.c. dose of either PBS-vehicle or 30 µg/kg SEQ ID NO: 13. Further blood samples were harvested atminute - SEQ ID NO: 13 treated animals exhibited an acute decrease in blood glucose concentrations and reached lowest levels approximately 8 hours post dose (
Figure 20 ). Twentyfour hours post-dose mean blood glucose concentrations of SEQ ID NO: 13 treated animals were close to baseline (Figure 20 ). Single treatment of diabetic db/db mice with 30 µg/kg SEQ ID NO: 13 resulted in a statistically significant reduction in the blood glucose AUC compared to the Diabetic-Vehicle group (One-Way ANOVA and Tukey Test,Figure 21 , Table 12). - Data are depicted as means±SEM. Statistical analyses were performed with Sigmaplot 12.5. A One-Way ANOVA and Tukey Test was used for pairwise multiple comparisons of all groups (n=8/group). When the difference in the mean values of the two groups was greater than 0.05 they were considered statistically significantly different. Lean-Vehicle group data are depicted in the Figures serving as a reference dataset for the non-obese state.
Table 12. Effects resulting from a single dose SEQ ID NO: 13 in fed, female db/db mice. Data are means±SEM. One-Way ANOVA and Tukey Test. n=8/group. Example Dose Diabetic-Vehicle Once PBS DIO-SEQ ID NO: 13 Once 30 µg/kg Plasma glucose area under the curve (mmol/L in 24 h) +646.38 ± 45.04 +458.34 ± 27.11 P<0.001 vs. Diabetic-Vehicle Table 13. Sequences SEQ. ID sequence 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 -
- <110> SANOFI
- <120> New compounds as peptidic as GLP1/Glucagon/GIP Receptor Agonists
- <130> DE2016/078WOPCT
- <160> 23
- <170> PatentIn version 3.5
- <210> 1
<211> 30
<212> PRT
<213> Homo sapiens - <220>
<221> MOD_RES
<222> (30)..(30)
<223> AMIDATION - <400> 1
- <210> 2
<211> 31
<212> PRT
<213> Artificial Sequence - <220>
<223> liraglutide - <220>
<221> MOD_RES
<222> (20)..(20)
<223> Lys is derivatized at N6 with (S)-4-Carboxy-4-hexadecanoylamino-butyryl- - <400> 2
- <210> 3
<211> 29
<212> PRT
<213> Homo sapiens - <400> 3
- <210> 4
<211> 39
<212> PRT
<213> Heloderma suspectum - <220>
<221> MOD_RES
<222> (39)..(39)
<223> AMIDATION - <400> 4
- <210> 5
<211> 42
<212> PRT
<213> Homo sapiens - <400> 5
- <210> 6
<211> 39
<212> PRT
<213> Artificial Sequence - <220>
<223> Exendin-4 derivative - <220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (14)..(14)
<223> Lys is derivatized at N6 with (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl- - <220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa = Aib - <220>
<221> misc_feature
<222> (34)..(34)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (39)..(39)
<223> AMIDATION - <400> 6
- <210> 7
<211> 39
<212> PRT
<213> Artificial Sequence - <220>
<223> Exendin-4 derivative - <220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (14)..(14)
<223> Lys is derivatized at N6 with (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl- - <220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa = Aib - <220>
<221> misc_feature
<222> (29).. (29)
<223> Xaa = dAla - <220>
<221> misc_feature
<222> (34)..(34)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (39)..(39)
<223> AMIDATION - <400> 7
- <210> 8
<211> 39
<212> PRT
<213> Artificial Sequence - <220>
<223> Exendin-4 derivative - <220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (14)..(14)
<223> Lys is derivatized at N6 with (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl- - <220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa = Aib - <220>
<221> misc_feature
<222> (34)..(34)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (39)..(39)
<223> AMIDATION - <400> 8
- <210> 9
<211> 39
<212> PRT
<213> Artificial Sequence - <220>
<223> Exendin-4 derivative - <220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (14)..(14)
<223> Lys is derivatized at N6 with (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl- - <220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa = Aib - <220>
<221> misc_feature
<222> (34)..(34)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (39)..(39)
<223> AMIDATION - <400> 9
- <210> 10
<211> 39
<212> PRT
<213> Artificial Sequence - <220>
<223> Exendin-4 derivative - <220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (14)..(14)
<223> Lys is derivatized at N6 with (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl- - <220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa = Aib - <220>
<221> misc_feature
<222> (29)..(29)
<223> Xaa = dAla - <220>
<221> misc_feature
<222> (34)..(34)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (39)..(39)
<223> AMIDATION - <400> 10
- <210> 11
<211> 39
<212> PRT
<213> Artificial Sequence - <220>
<223> Exendin-4 derivative - <220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (14)..(14)
<223> Lys is derivatized at N6 with (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl- - <220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa = Aib - <220>
<221> misc_feature
<222> (29)..(29)
<223> Xaa = dAla - <220>
<221> misc_feature
<222> (34)..(34)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (39)..(39)
<223> AMIDATION - <400> 11
- <210> 12
<211> 39
<212> PRT
<213> Artificial Sequence - <220>
<223> Exendin-4 derivative - <220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (14)..(14)
<223> Lys is derivatized at N6 with (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl- - <220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa = Aib - <220>
<221> misc_feature
<222> (34)..(34)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (39)..(39)
<223> AMIDATION - <400> 12
- <210> 13
<211> 39
<212> PRT
<213> Artificial Sequence - <220>
<223> Exendin-4 derivative - <220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (14)..(14)
<223> Lys is derivatized at N6 with (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl- - <220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa = Aib - <220>
<221> misc_feature
<222> (29).. (29)
<223> Xaa = dAla - <220>
<221> misc_feature
<222> (34)..(34)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (39)..(39)
<223> AMIDATION - <400> 13
- <210> 14
<211> 39
<212> PRT
<213> Artificial Sequence - <220>
<223> Exendin-4 derivative - <220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (14)..(14)
<223> Lys is derivatized at N6 with (S)-4-Carboxy-4-hexadecanoylamino-butyryl- - <220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa = Aib - <220>
<221> misc_feature
<222> (34)..(34)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (39)..(39)
<223> AMIDATION - <400> 14
- <210> 15
<211> 39
<212> PRT
<213> Artificial Sequence - <220>
<223> Exendin-4 derivative - <220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (14)..(14)
<223> Lys is derivatized at N6 with (S)-4-Carboxy-4-octadecanoylamino-butyryl- - <220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa = Aib - <220>
<221> misc_feature
<222> (34)..(34)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (39)..(39)
<223> AMIDATION - <400> 15
- <210> 16
<211> 39
<212> PRT
<213> Artificial Sequence - <220>
<223> Exendin-4 derivative - <220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (14)..(14)
<223> Lys is derivatized at N6 with [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[2-[2-[2-(hexadecanoylamin o)ethoxy]ethoxy]acetyl]amino]butyrylamino]-butyryl- - <220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa = Aib - <220>
<221> misc_feature
<222> (34)..(34)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (39)..(39)
<223> AMIDATION - <400> 16
- <210> 17
<211> 39
<212> PRT
<213> Artificial Sequence - <220>
<223> Exendin-4 derivative - <220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (14)..(14)
<223> Lys is derivatized at N6 with [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[2-[2-[2-(hexadecanoylamin o)ethoxy]ethoxy]acetyl]amino]butyrylamino]-butyryl- - <220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa = Aib - <220>
<221> misc_feature
<222> (29).. (29)
<223> Xaa = dAla - <220>
<221> misc_feature
<222> (34)..(34)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (39)..(39)
<223> AMIDATION - <400> 17
- <210> 18
<211> 39
<212> PRT
<213> Artificial Sequence - <220>
<223> Exendin-4 derivative - <220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (14)..(14)
<223> Lys is derivatized at N6 with [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[2-[2-[2-(hexadecanoylamin o)ethoxy]ethoxy]acetyl]amino]butyrylamino]-butyryl- - <220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa = Aib - <220>
<221> misc_feature
<222> (34)..(34)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (39)..(39)
<223> AMIDATION - <400> 18
- <210> 19
<211> 39
<212> PRT
<213> Artificial Sequence - <220>
<223> Exendin-4 derivative - <220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (14)..(14)
<223> Lys is derivatized at N6 with [[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[2-[2-[2-(hexadecanoylamin o)ethoxy]ethoxy]acetyl]amino]butyrylamino]-butyryl- - <220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa = Aib - <220>
<221> misc_feature
<222> (29)..(29)
<223> Xaa = dAla - <220>
<221> misc_feature
<222> (34)..(34)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (39)..(39)
<223> AMIDATION - <400> 19
- <210> 20
<211> 39
<212> PRT
<213> Artificial Sequence - <220>
<223> Exendin-4 derivative - <220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (14)..(14)
<223> Lys is derivatized at N6 with (4S)-Carboxy-[2-(2-{2-[(4R)-5-carboxy-4-hexadecanoylamino-pentanoylamino]-etho xy}-ethoxy)-acetylamino]-butyryl - <220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa = Aib - <220>
<221> misc_feature
<222> (34)..(34)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (39)..(39)
<223> AMIDATION - <400> 20
- <210> 21
<211> 39
<212> PRT
<213> Artificial Sequence - <220>
<223> Exendin-4 derivative - <220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (14)..(14)
<223> Lys is derivatized at N6 with (4S)-Carboxy-[2-(2-{2-[(4R)-5-carboxy-4-hexadecanoylamino-pentanoylamino]-etho xy}-ethoxy)-acetylamino]-butyryl - <220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa = Aib - <220>
<221> misc_feature
<222> (29)..(29)
<223> Xaa = dAla - <220>
<221> misc_feature
<222> (34)..(34)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (39)..(39)
<223> AMIDATION - <400> 21
- <210> 22
<211> 39
<212> PRT
<213> Artificial Sequence - <220>
<223> Exendin-4 derivative - <220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (14)..(14)
<223> Lys is derivatized at N6 with (4S)-Carboxy-[2-(2-{2-[(4R)-5-carboxy-4-hexadecanoylamino-pentanoylamino]-etho xy}-ethoxy)-acetylamino]-butyryl - <220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa = Aib - <220>
<221> misc_feature
<222> (34)..(34)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (39)..(39)
<223> AMIDATION - <400> 22
- <210> 23
<211> 39
<212> PRT
<213> Artificial Sequence - <220>
<223> Exendin-4 derivative - <220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (14)..(14)
<223> Lys is derivatized at N6 with (4S)-Carboxy-[2-(2-{2-[(4R)-5-carboxy-4-hexadecanoylamino-pentanoylamino]-etho xy}-ethoxy)-acetylamino]-butyryl - <220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa = Aib - <220>
<221> misc_feature
<222> (29).. (29)
<223> Xaa = dAla - <220>
<221> misc_feature
<222> (34)..(34)
<223> Xaa = Aib - <220>
<221> MOD_RES
<222> (39)..(39)
<223> AMIDATION - <400> 23
Claims (15)
- A compound of the formula I: whereinX14 represents an amino acid residue with a functionalized -NH2 side chain group, selected from the group consisting of Lys, Orn, Dab, or Dap, wherein the -NH2 side chain group is functionalized by -Z-C(O)-R5, wherein Z represents a linker in all stereoisomeric forms and R5 is a moiety comprising up to 50 carbon atoms and heteroatoms selected from N and O,X16 represents an amino acid residue selected from Glu and Lys,X29 represents an amino acid residue selected from D-Ala and Gly,X31 represents an amino acid residue selected from His and Pro,R1 is NH2 or OH, particularly NH2,or a salt or solvate thereof.
- The compound according to claim 1, wherein the peptidic compound has a relative activity of at least 1% compared to that of natural glucagon at the glucagon receptor, and/or wherein the peptidic compound exhibits a relative activity of at least 10% compared to that of GLP-1(7-36)-amide at the GLP-1 receptor, and/or wherein the peptidic compound exhibits a relative activity of at least 2% compared to that of GIP at the GIP receptor, as determined by the capability to stimulate intracellular cAMP formation.
- The compound of claim 1 or 2, whereinX14 represents Lys wherein the -NH2 side chain group is functionalized with a group -Z-C(O)R5 , whereinZ represents a group selected from gGlu, gGlu-gGlu, gGlu-AEEAc-gAAA-, gGlu-gGlu-AEEAc, AEEAc-AEEAc-gGlu and AEEAc-AEEAc-AEEAc; and R5 represents a group selected from pentadecanyl or heptadecanyl, or whereinX14 represents Lys wherein the -NH2 side chain group is functionalized with a group -Z-C(O)R5 , whereinZ represents a group selected from gGlu, gGlu-gGlu, gGlu-AEEAc-gAAA- and gGlu-gGlu-AEEAc; andR5 represents a group selected from pentadecanyl or heptadecanyl.
- The compound of any one of claims 1 to 3, whereinX14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-R1 represents NH2,or a salt or solvate thereof.
- The compound of any one of claims 1 to 3,
whereinX14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl,R1 represents NH2,or a salt or solvate thereof. - The compound of any one of claims 1 to 5, whereinX14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylam ino-butyrylamino)-butyryl-,X16 represents an amino acid residue selected from Glu and Lys,X29 represents an amino acid residue selected from D-Ala and Gly,X31 represents an amino acid residue selected from His and Pro,R1 represents NH2;or a salt or solvate thereof.
- The compound of any one of claims 1 to 5, whereinX14 represents Lys wherein the -NH2 side chain group is functionalized by (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,(S)-4-Carboxy-4-octadecanoylamino-butyryl-, R1 represents NH2; and wherein(i) X16 represents an amino acid residue selected from Glu and Lys, X29 represents Gly, X31 represents an amino acid residue selected from His and Pro,
or wherein(ii) X16 represents Lys, X29 represents an amino acid residue selected from D-Ala and Gly, X31 represents an amino acid residue selected from His and Pro,
or wherein(iii) X16 represents an amino acid residue selected from Glu and Lys, X29 represents an amino acid residue selected from D-Ala and Gly, X31 represents Pro,or a salt or solvate thereof. - The compound of any one of claims 1 to 7, selected from the compounds of SEQ ID NO: 6-23, as well as salts or solvates thereof.
- The compound of claim 1, wherein the compound is represented bySEQ ID NO.: 6 or a salt or solvate thereof,SEQ ID NO.: 9 or a salt or solvate thereof, orSEQ ID NO.: 11 or a salt or solvate thereof.
- The compound of any one of claims 1 to 9 for use as pharmaceutical.
- The compound of any one of claims 1 to 9 together with at least one additional therapeutically active agent for use as pharmaceutical.
- A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 9 or a physiologically acceptable salt or solvate of any of them, for use as a pharmaceutical, wherein said pharmaceutical composition optionally comprises at least one additional pharmaceutically active ingredient.
- The compound of any one of claims 1 to 9 for use in a method of treating glucose intolerance, insulin resistance, pre-diabetes, increased fasting glucose, hyperglycemia, type 2 diabetes, hypertension, dyslipidemia, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke or any combination of these individual disease components.
- The compound of any one of claims 1 to 9 for use in a method of treating or preventing hepatosteatosis, orfor use in a method of treating or preventing hyperglycemia, diabetes and obesity, e.g.simultaneously treating diabetes and obesity, ortreating type 2 diabetes, ortreating obesity.
- The compound of formula I as claimed in any one of claims 1 to 9 and an effective amount of at least one additional active ingredient,for use in a method of treating hyperglycemia, type 2 diabetes or obesity, particularlywherein an effective amount of at least one compound of formula I and the additional active ingredient are for simultaneous or for sequential administration.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP16306605 | 2016-12-02 | ||
PCT/EP2017/081126 WO2018100135A1 (en) | 2016-12-02 | 2017-12-01 | New compounds as peptidic glp1/glucagon/gip receptor agonists |
Publications (2)
Publication Number | Publication Date |
---|---|
EP3548062A1 EP3548062A1 (en) | 2019-10-09 |
EP3548062B1 true EP3548062B1 (en) | 2022-01-12 |
Family
ID=57542936
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP17821489.6A Active EP3548062B1 (en) | 2016-12-02 | 2017-12-01 | New compounds as peptidic glp1/glucagon/gip receptor agonists |
Country Status (14)
Country | Link |
---|---|
US (1) | US10519211B2 (en) |
EP (1) | EP3548062B1 (en) |
JP (1) | JP6987139B2 (en) |
KR (1) | KR20190086022A (en) |
CN (1) | CN109996557B (en) |
AR (1) | AR110301A1 (en) |
AU (1) | AU2017369691A1 (en) |
BR (1) | BR112019011144A2 (en) |
CA (1) | CA3045474A1 (en) |
IL (1) | IL266985A (en) |
MX (1) | MX2019006427A (en) |
RU (1) | RU2019120203A (en) |
TW (1) | TW201833131A (en) |
WO (1) | WO2018100135A1 (en) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW201833132A (en) * | 2016-12-02 | 2018-09-16 | 法商賽諾菲公司 | New compounds as peptidic trigonal glp1/glucagon/gip receptor agonists |
HUE060135T2 (en) | 2018-04-05 | 2023-02-28 | Sun Pharmaceutical Ind Ltd | Novel glp-1 analogues |
TW202015735A (en) | 2018-05-30 | 2020-05-01 | 法商賽諾菲公司 | Conjugates comprising an glp-1/glucagon/gip triple receptor agonist, a linker and hyaluronic acid |
JP2022515229A (en) * | 2018-12-21 | 2022-02-17 | ハンミ ファーマシューティカル カンパニー リミテッド | A pharmaceutical composition comprising insulin and a triple active agent having activity on all of glucagon, GLP-1 and GIP receptors. |
TWI764209B (en) * | 2019-08-01 | 2022-05-11 | 美商美國禮來大藥廠 | Gipr-agonist compounds |
CA3148347A1 (en) | 2019-08-19 | 2021-02-25 | Michael E. Kopach | Methods of making incretin analogs |
JP2022551282A (en) * | 2019-10-04 | 2022-12-08 | ハンミ ファーマシューティカル カンパニー リミテッド | Compositions Comprising Glucagon and GLP-1 Receptor and GIP Receptor Dual Agonists and Therapeutic Uses Thereof |
CA3156452A1 (en) | 2019-11-11 | 2021-05-20 | Boehringer Ingelheim International Gmbh | Npy2 receptor agonists |
KR20230045088A (en) | 2020-08-07 | 2023-04-04 | 베링거 인겔하임 인터내셔날 게엠베하 | Soluble NPY2 receptor agonists |
WO2022159395A1 (en) | 2021-01-20 | 2022-07-28 | Viking Therapeutics, Inc. | Compositions and methods for the treatment of metabolic and liver disorders |
CN115975057B (en) * | 2023-03-16 | 2023-05-16 | 杭州信海医药科技有限公司 | Solid phase synthesis method of trastuzumab |
Family Cites Families (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2003268621B2 (en) | 2002-10-02 | 2009-01-15 | Zealand Pharma A/S | Stabilized exendin-4 compounds |
US20080019911A1 (en) | 2005-04-20 | 2008-01-24 | Aimin Xu | Method for decreasing blood glucose and improving glucose tolerance using angiopoietin-like protein 4 |
ES2385093T3 (en) | 2005-06-13 | 2012-07-18 | Imperial Innovations Limited | Oxintomodulin analogues and their effects on eating behavior |
PE20100056A1 (en) | 2008-06-17 | 2010-01-26 | Univ Indiana Res & Tech Corp | GLUCAGON ANALOGS AS GIP AGONISTS |
SG176858A1 (en) | 2009-06-16 | 2012-02-28 | Univ Indiana Res & Tech Corp | Gip receptor-active glucagon compounds |
AU2011202239C1 (en) | 2010-05-19 | 2017-03-16 | Sanofi | Long-acting formulations of insulins |
ES2713952T3 (en) | 2010-12-22 | 2019-05-24 | Univ Indiana Res & Tech Corp | Glucagon analogs showing GIP receptor activity |
TWI599575B (en) | 2012-06-21 | 2017-09-21 | 印第安納大學科技研究公司 | Glucagon analogs exhibiting gip receptor activity |
TR201808818T4 (en) | 2012-06-21 | 2018-07-23 | Novo Nordisk As | Glucagon analogs exhibiting gip receptor activity. |
WO2014049610A2 (en) | 2012-09-26 | 2014-04-03 | Cadila Healthcare Limited | Peptides as gip, glp-1 and glucagon receptors triple-agonist |
UA116217C2 (en) * | 2012-10-09 | 2018-02-26 | Санофі | Exendin-4 derivatives as dual glp1/glucagon agonists |
RU2652783C2 (en) * | 2012-12-21 | 2018-05-03 | Санофи | Dual glp1/gip or trigonal glp1/gip/glucagon agonists |
TR201902516T4 (en) | 2013-11-06 | 2019-03-21 | Zealand Pharma As | Glucagon-glp-1-envy triple agonist compounds. |
EP3080151A1 (en) | 2013-12-13 | 2016-10-19 | Sanofi | Exendin-4 peptide analogues |
TW201609797A (en) | 2013-12-13 | 2016-03-16 | 賽諾菲公司 | Dual GLP-1/glucagon receptor agonists |
TW201609800A (en) | 2013-12-13 | 2016-03-16 | 賽諾菲公司 | EXENDIN-4 peptide analogues as dual GLP-1/glucagon receptor agonists |
TW201625669A (en) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | Peptidic dual GLP-1/glucagon receptor agonists derived from Exendin-4 |
WO2016198624A1 (en) | 2015-06-12 | 2016-12-15 | Sanofi | Exendin-4 derivatives as trigonal glp-1/glucagon/gip receptor agonists |
TW201833132A (en) | 2016-12-02 | 2018-09-16 | 法商賽諾菲公司 | New compounds as peptidic trigonal glp1/glucagon/gip receptor agonists |
-
2017
- 2017-11-30 AR ARP170103363A patent/AR110301A1/en unknown
- 2017-11-30 TW TW106141761A patent/TW201833131A/en unknown
- 2017-12-01 KR KR1020197018793A patent/KR20190086022A/en unknown
- 2017-12-01 CA CA3045474A patent/CA3045474A1/en not_active Abandoned
- 2017-12-01 EP EP17821489.6A patent/EP3548062B1/en active Active
- 2017-12-01 BR BR112019011144A patent/BR112019011144A2/en not_active Application Discontinuation
- 2017-12-01 RU RU2019120203A patent/RU2019120203A/en not_active Application Discontinuation
- 2017-12-01 CN CN201780073307.6A patent/CN109996557B/en active Active
- 2017-12-01 AU AU2017369691A patent/AU2017369691A1/en not_active Abandoned
- 2017-12-01 MX MX2019006427A patent/MX2019006427A/en unknown
- 2017-12-01 WO PCT/EP2017/081126 patent/WO2018100135A1/en unknown
- 2017-12-01 US US15/829,698 patent/US10519211B2/en active Active
- 2017-12-01 JP JP2019529534A patent/JP6987139B2/en active Active
-
2019
- 2019-05-29 IL IL266985A patent/IL266985A/en unknown
Non-Patent Citations (1)
Title |
---|
None * |
Also Published As
Publication number | Publication date |
---|---|
US10519211B2 (en) | 2019-12-31 |
EP3548062A1 (en) | 2019-10-09 |
AU2017369691A1 (en) | 2019-07-18 |
CN109996557A (en) | 2019-07-09 |
CA3045474A1 (en) | 2018-06-07 |
JP6987139B2 (en) | 2021-12-22 |
TW201833131A (en) | 2018-09-16 |
KR20190086022A (en) | 2019-07-19 |
JP2019536795A (en) | 2019-12-19 |
RU2019120203A (en) | 2021-01-14 |
CN109996557B (en) | 2024-05-03 |
WO2018100135A1 (en) | 2018-06-07 |
US20180155407A1 (en) | 2018-06-07 |
AR110301A1 (en) | 2019-03-13 |
IL266985A (en) | 2019-07-31 |
MX2019006427A (en) | 2019-08-21 |
BR112019011144A2 (en) | 2019-10-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3548508B1 (en) | New compounds as peptidic trigonal glp1/glucagon/gip receptor agonists | |
EP3548062B1 (en) | New compounds as peptidic glp1/glucagon/gip receptor agonists | |
CN106414488B (en) | Peptide dual GLP-1/glucagon receptor agonists derived from exendin-4 | |
CN106715466B (en) | Exendin-4 derivatives as selective glucagon receptor agonists | |
EP3319982B1 (en) | New exendin-4 derivatives as selective peptidic dual glp-1 / glucagon receptor agonists | |
AU2021229621B2 (en) | Peptides as selective GIP receptor agonists | |
EP4399224A1 (en) | New peptides as potent and selective gip receptor agonists | |
EA040723B1 (en) | NEW COMPOUNDS AS PEPTIDE TRIPLE AGONISTS OF GLP-1/GLUCAGON/GIP RECEPTORS |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: UNKNOWN |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20190702 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
AX | Request for extension of the european patent |
Extension state: BA ME |
|
RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: PFEIFFER-MAREK, STEFANIA Inventor name: HAACK, TORSTEN Inventor name: WAGNER, MICHAEL Inventor name: LORENZ, MARTIN Inventor name: EVERS, ANDREAS Inventor name: LORENZ, KATRIN Inventor name: BOSSART, MARTIN Inventor name: KADEREIT, DIETER |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) | ||
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
17Q | First examination report despatched |
Effective date: 20200512 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: GRANT OF PATENT IS INTENDED |
|
INTG | Intention to grant announced |
Effective date: 20210823 |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE PATENT HAS BEEN GRANTED |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R096 Ref document number: 602017052323 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: REF Ref document number: 1461947 Country of ref document: AT Kind code of ref document: T Effective date: 20220215 |
|
REG | Reference to a national code |
Ref country code: LT Ref legal event code: MG9D |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: MP Effective date: 20220112 |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: MK05 Ref document number: 1461947 Country of ref document: AT Kind code of ref document: T Effective date: 20220112 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 Ref country code: RS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 Ref country code: PT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220512 Ref country code: NO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220412 Ref country code: LT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 Ref country code: HR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 Ref country code: ES Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 Ref country code: BG Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220412 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: PL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 Ref country code: LV Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220413 Ref country code: FI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 Ref country code: AT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220512 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R097 Ref document number: 602017052323 Country of ref document: DE |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SM Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 Ref country code: SK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 Ref country code: RO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 Ref country code: EE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 Ref country code: DK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 Ref country code: CZ Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: AL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 |
|
26N | No opposition filed |
Effective date: 20221013 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
REG | Reference to a national code |
Ref country code: BE Ref legal event code: MM Effective date: 20221231 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20221201 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20221231 Ref country code: IE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20221201 Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20221231 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20221231 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 20230929 Year of fee payment: 7 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 20231012 Year of fee payment: 7 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DE Payment date: 20231003 Year of fee payment: 7 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: HU Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO Effective date: 20171201 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CY Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MC Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MC Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220112 |